Gene Regulation Landscape — detailed construction notes

From DNA to proteins — reductionist architecture (v7)

Clawd · 2026-05-01 / updated 2026-06-21 · 37 mechanisms · 2 meta-principles · 7 layers

These notes are the technical companion to the current Gene Regulation Landscape v7 graph. They document the 37 mechanism boxes, 2 meta-principles, 89 mechanism relations, and 7 meta-style annotations used in the rendered figure. The rendered figure was generated from the Graphviz source file gene-reg-v7.dot.

Executive Summary

Cells regulate gene expression across 7 nested levels, from three-dimensional genome organization to selective protein clearance. The graph contains 37 distinct mechanism boxes plus 2 cross-cutting meta-principles, LLPS and DECAY, shown as border styles on the mechanisms they affect. Across the map, most mechanisms reduce to three recurring strategies: (A) controlling physical accessibility, (B) writing and reading reversible marks, and (C) kinetic coupling between processes.

How To Read These Notes

Graph Notation And Abbreviations

Term Meaning
tx Transcription. The graph avoids using it for translation to prevent ambiguity.
co-tx Co-transcriptional: coupled to Pol II progression or nascent RNA.
A Accessibility principle: making a substrate available or unavailable.
B Mark/reader principle: a reversible mark has effects depending on its reader and context.
C Kinetic-coupling principle: the speed of one process changes the outcome of another.
⊣ Repression, inhibition, or direct blocking.
(back) Feedback or relation back to an upstream layer.
(bidirectional) Reciprocal relation represented as two-way coupling.
(**) Especially important kinetic coupling linked to principle C.
initiation ↑ Increased translation initiation.
RQC Ribosome-associated quality control; surveillance of stalled ribosomes and nascent-peptide degradation.
NGD No-go decay; decay triggered by a ribosome stalled on an mRNA.
NSD Non-stop decay; decay triggered by an mRNA without a functional stop codon.
SUMO Small ubiquitin-like modifier; a small protein conjugated to substrates as a post-translational mark.
NEDDylation NEDD8 conjugation, especially on cullins to activate CRL E3 ligases.
bold In the image, the top text in each box is the mechanism code name and maps 1-to-1 to the glossary.
italics In the image and descriptions, italics are used for gene/protein names when helpful; graph boxes remain mechanism names.

Glossary Of Non-Gene Concepts

Term Meaning
A/B compartments Chromatin domains seen by Hi-C; A is usually active/euchromatic, B inactive/heterochromatic.
TAD Topologically associating domain; a chromatin neighborhood insulated by boundaries such as CTCF/cohesin.
Enhancer-promoter loop 3D contact bringing a distal enhancer close to a target promoter.
Super-enhancer Dense enhancer cluster enriched in master TFs, Mediator, BRD4, and Pol II.
Condensate / LLPS Liquid-liquid phase separation that concentrates molecules into a dense non-membrane phase.
DNA methylation Addition of methyl groups to DNA, often linked to promoter repression.
Histone mark Chemical histone modification, such as acetylation or methylation, read by chromatin proteins.
Chromatin remodeling ATP-dependent repositioning, eviction, or exchange of nucleosomes.
ncRNA Functional non-coding RNA not translated into protein.
Pol II pausing Promoter-proximal RNA polymerase II pause before productive elongation.
CTD phosphorylation Phosphorylation of the Pol II CTD tail, coordinating transcription and RNA processing.
5’ capping Addition of an m7G cap to nascent RNA, required for protection, export, and translation.
Alternative splicing Regulated exon choice producing multiple isoforms from one gene.
Alternative polyadenylation Use of different cleavage/polyA sites, often changing 3’UTR length.
A-to-I editing Adenosine-to-inosine RNA editing; inosine is often read as guanosine.
m6A N6-methyladenosine, a reversible RNA modification interpreted by reader proteins.
RBP RNA-binding protein.
miRNA-RISC MicroRNA loaded into RISC to repress or destabilize target mRNAs.
ceRNA Competing endogenous RNA; an RNA that can buffer miRNAs through shared target sites when abundance, affinity, and colocalization are sufficient.
NMD Nonsense-mediated decay; surveillance and degradation of transcripts with premature stop codons.
Deadenylation / decapping Removal of the polyA tail and 5’ cap, usually committing an mRNA to decay.
RNA G-quadruplex Guanine-rich RNA structure that can block scanning or alter RNA fate.
Stress granule / P-body Cytoplasmic RNA-protein condensates involved in RNA storage, repression, or decay.
Cap-dependent translation Canonical initiation through cap recognition followed by 5’UTR scanning.
ISR / eIF2α-P Integrated stress response; eIF2α phosphorylation lowers global initiation but favors selected mRNAs.
uORF Upstream open reading frame in a 5’UTR that can divert scanning ribosomes.
IRES / ITAF Internal ribosome entry site and helper factors. Viral IRESs are strong examples; many cellular IRES claims need context-specific validation.
RQC / NGD / NSD Ribosome quality control, no-go decay, and non-stop decay; surveillance of abnormal translation.
O-GlcNAc Reversible sugar modification on Ser/Thr residues that can crosstalk with phosphorylation.
Ubiquitin chain Ubiquitin polymer whose linkage type, such as K48 or K63, helps determine protein fate.
SUMOylation SUMO conjugation, often involved in nuclear interactions and complex assembly.
Neddylation NEDD8 conjugation, mostly on cullins, activating CRL E3 ligases.
Proteasome Proteolytic complex that degrades many short-lived or damaged ubiquitinated proteins.
Selective autophagy Lysosomal clearance of specific cargoes: aggregates, organelles, or ubiquitinated complexes.
UPR Unfolded protein response; ER-stress response.
PAR / ADP-ribosylation Poly-ADP-ribose signaling, often around DNA damage and condensate formation.

Reductionist Architecture — Three Core Strategies

Strategy A — ACCESSIBILITY CONTROL
  "Make a substrate accessible or inaccessible to its machinery"
  Examples: OPENER/SHUFFLER -> TF access
            FENCES/BRIDGES -> enhancer-promoter proximity
            DARTS/SPONGE -> mRNA availability
            VAULT -> translational access

Strategy B — REVERSIBLE MARK + CONTEXTUAL READING
  "The same mark has different effects depending on its reader and context"
  Examples: SILENCER/WRITER-A/WRITER-R (histone code + DNA methylation)
            STAMP (m6A -> YTHDF1 or YTHDF2 depending on context)
            ROUTER (K48 -> proteasome; K63 -> signaling/autophagy)
            SWITCH (phosphorylation -> activation or degradation depending on substrate)

Strategy C — KINETIC COUPLING
  "The speed of process A determines the output of process B"
  Examples: Pol II rate -> SPLICER
            H3K36me3 deposited by SCRIBE -> SPLICER
            limiting ternary complex (BRAKE) -> DECOY bypass -> selective ATF4 FORGE
            codon pausing (TEMPO) -> co-translational MATURE

Graph Box Map

Layer Mechanisms
0 — 3D genome ZONES, FENCES, BRIDGES, HUBS
1 — Epigenetics SILENCER, OPENER, WRITER-A, WRITER-R, SHUFFLER, GUIDES
2 — Transcription KEYS, SCRIBE
3 — Co-transcriptional SHIELD, SPLICER, TRIMMER, RECODER
4 — Post-transcriptional STAMP, READERS, DARTS, SPONGE, CENSOR, TIMER, CLIPS, VAULT
5 — Translational FORGE, BRAKE, DECOY, BYPASS, TEMPO, INSPECTOR
6 — Post-translational SWITCH, ROUTER, TETHER, LICENSE, DESTROY, MATURE, PAR
Meta LLPS, DECAY

Mechanisms Intentionally Abstracted Or Not Drawn As Boxes

The v7 map is a high-level Pol II/mRNA-centered gene-expression landscape, not an exhaustive catalogue of every molecular state that affects regulation. Several important mechanisms are therefore treated as cross-layer constraints, caveats, or candidate v2 annotations rather than separate boxes:

Mechanism or axis Why it matters Current placement / v2 handling
R-loops / RNA:DNA hybrids Nascent RNA can hybridize with template DNA, affecting transcription, chromatin, replication conflicts, and genome instability. Not a current box. Add as a cross-layer note around SCRIBE, GUIDES, and PAR; strongest when discussing co-transcriptional genome stress rather than generic RNA fate.
DNA supercoiling / torsional stress / topoisomerases Pol II movement and enhancer-promoter activity generate and respond to torsional stress; topoisomerases can tune elongation and chromatin accessibility. Cross-layer physical constraint near SCRIBE, BRIDGES, and FENCES; not a modular regulatory layer at current resolution.
Transcription-replication conflicts Collisions between transcription and replication can create DNA damage, R-loops, fork stress, and selection against certain transcriptional states. Mostly outside the expression-control scope; mention near SCRIBE and PAR as a genome-stability extension.
Alternative promoter / TSS choice Which promoter or start site is used changes 5’UTRs, isoforms, regulatory inputs, and sometimes protein N-termini. Important named output, but do not add as a box by default. Reduce to KEYS, chromatin accessibility/marks, BRIDGES/HUBS, and SCRIBE unless a future map specifically focuses on promoter architecture.
Transcription termination and readthrough Termination, pause-release failure, and readthrough shape antisense transcription, downstream gene interference, 3’ processing, and chromatin state. Important named output, but reduce first to SCRIBE, TRIMMER, TIMER, and chromatin-context edges; add a node only if termination machinery itself becomes central.
RNA nuclear export / nuclear retention Mature RNAs do not automatically reach the cytoplasm; export competence and retention alter the expressed transcriptome. Important named output/checkpoint, but reduce first to SHIELD, SPLICER, TRIMMER, STAMP, READERS, and nuclear-retention/LLPS logic; add EXPORT/GATE only if export machinery needs explicit treatment.
Nuclear bodies and subnuclear organization Speckles, paraspeckles, nucleoli, Cajal bodies, and other compartments concentrate processing or retention factors. Covered only indirectly through LLPS/condensate language. Candidate cross-layer annotation rather than one universal box.
RNA modifications beyond m6A and A-to-I Pseudouridine, m5C, m1A, ac4C, and 2’-O-methylation can affect RNA stability, translation, structure, or immune recognition. Add as scope note under STAMP; m6A remains the main drawn example because it has the clearest broad mRNA regulatory literature.
Repeats, transposons, and repeat-derived regulatory elements Transposons are silenced by piRNA/DNA methylation pathways, supply regulatory DNA, and can produce dsRNA or innate-immune triggers. Add to GUIDES/SILENCER caveats; repeat-derived enhancers also touch KEYS/BRIDGES.
Enhancer/promoter motif grammar TF motif identity, spacing, orientation, affinity, and cooperative syntax help determine which enhancers and promoters are active. Not a GUIDES mechanism; best treated as a KEYS/BRIDGES design principle.
Pol I/Pol III, rRNA/tRNA abundance, and ribosome biogenesis rRNA/tRNA production and ribosome biogenesis set translational capacity and growth-state feedback; MYC/mTOR/nutrient signaling couple this to broader gene-expression programs. Mostly outside the Pol II/mRNA map. Existing TEMPO covers tRNA abundance and rRNA/ribosome heterogeneity at translation; a separate node would only be justified in a growth/ribosome-biogenesis-expanded map.

Reduction rule for named checkpoint events

Some named events are biologically important but should not automatically become new boxes. The map is meant to reduce regulation to underlying mechanisms. If an event is fully explained by existing mechanisms, the right action is to make sure those mechanisms and their edges are present, not to add a redundant event node.

Decision note: for v7/v8, prefer this reductionist treatment for promoter/TSS choice, termination, and export/retention unless a review goal specifically requires the named event as its own module.

I. The 7 Layers — Explanations And Mechanisms

Layer 0 — 3D Genome

The genome is not linear but three-dimensional. Spatial organization determines which enhancers can communicate with which promoters.

Code name Full name Exact definition
ZONES A/B compartments Large chromatin regions (~5-20 Mb) detected by Hi-C. A compartments are transcriptionally active euchromatin (H3K27ac, H3K4me3). B compartments are inactive heterochromatin (H3K27me3, H3K9me3, DNA methylation, nuclear lamina). A↔B transitions accompany cell differentiation.
FENCES TADs (Topologically Associating Domains) Preferential interaction domains of ~0.1-2 Mb, often delimited by convergent CTCF boundaries. Dominant mechanism: cohesin extrudes loops until blocked by convergent CTCF pairs, producing partial inter-domain insulation. Boundaries strongly reduce aberrant enhancer-promoter contacts but do not always abolish them; expression effects depend on locus and cell type.
BRIDGES Enhancer-promoter loops Specific physical contacts between a distal enhancer and its target promoter, often but not exclusively within the same TAD. Mediated or stabilized, depending on context, by Mediator, cohesin, YY1, ZNF143, LDB1, and other factors. Can span over 1 Mb of linear distance.
HUBS Super-enhancers / Pol II condensates Clusters of ordinary enhancers spanning 5-50 kb and densely loaded with master TFs, BRD4, Mediator, and Pol II. They can form or feed coactivator-enriched transcriptional condensates, but “super-enhancer” as a ChIP-seq definition and “condensate” as a dynamic physical object are not strictly synonymous. Often drive cell-identity genes and some oncogenes.

Layer 1 — Epigenetics

Heritable or semi-stable chromatin changes that alter accessibility without changing DNA sequence.

Code name Full name Exact definition
SILENCER DNA methylation Addition of a methyl group to cytosine (5mC) at CpG dinucleotides. Writers: DNMT1 for replication maintenance, DNMT3A/3B for de novo methylation. Erasers: TET1/2/3 oxidize 5mC to 5hmC/5fC/5caC followed by BER. Readers: MBD proteins recruit HDACs and repress transcription. General effect: repression at promoter CpG islands; gene-body methylation can stabilize Pol II elongation.
OPENER Histone acetylation Acetyl groups added to histone lysines (H3K27ac, H3K9ac, H4K16ac). Writers: p300/CBP, GCN5, PCAF, MOF. Erasers: HDACs. Readers: bromodomains such as BRD4 and BRG1. Acetylation neutralizes Lys positive charge, weakens histone-DNA attraction, opens nucleosomes, and permits TF/Pol II access. H3K27ac marks active enhancers.
WRITER-A Activating histone methylation H3K4me3 at active promoters, H3K4me1 at enhancers, H3K36me3 in elongating gene bodies, H3K79me2 at telomeres/elongation. Writers: MLL1-4/KMT2A-D and SET1A/B for H3K4; SETD2 for H3K36me3 coupled to Pol II Ser2-P. Readers: PHD fingers for H3K4me3 and PWWP domains for H3K36me3. H3K36me3 recruits splicing regulators, linking chromatin state to exon choice.
WRITER-R Repressive histone methylation H3K27me3 for facultative Polycomb repression, H3K9me3 for constitutive heterochromatin, and H4K20me3 in heterochromatin. Writers: EZH1/2 in PRC2 for H3K27me3; SUV39H1/2 and SETDB1 for H3K9me3. Readers: CBX/PRC1 and HP1/CBX1/3/5. H3K27me3 and H3K27ac compete on the same residue, forming an activation/repression switch.
SHUFFLER ATP-dependent chromatin remodeling Complexes that use ATP to reposition, evict, or replace nucleosomes. Families include SWI/SNF (BAF/PBAF), ISWI, CHD, and INO80. They are recruited by TFs and by histone marks through reader modules.
GUIDES Epigenetic ncRNAs Small and long non-coding RNAs that guide chromatin-modifying complexes to target loci. piRNAs guide transposon silencing by de novo DNA methylation in the germline. lncRNA scaffolds such as XIST, HOTAIR, and KCNQ1OT1 recruit PRC2 or related complexes to regional chromatin targets. Repeat-derived RNAs and transposon-associated small-RNA pathways are included here when they guide silencing; repeat-derived enhancers or TF motif grammar instead belong to KEYS/BRIDGES.

Layer 2 — Transcription

Control of RNA polymerase II initiation and progression.

Code name Full name Exact definition
KEYS Transcription factors (TFs) Sequence-specific DNA-binding proteins with activation or repression domains. Activators recruit HATs, KMTs, CRCs, Mediator, and Pol II. Repressors recruit HDACs, PRC, or NuRD. Pioneer factors such as FOXA1, OCT4, and GATA3 can open compact chromatin. Master TFs such as OCT4, SOX2, and MYC define super-enhancers. TF motif grammar — motif identity, spacing, orientation, affinity, and cooperative syntax — helps decide enhancer and promoter usage, but is abstracted into this node rather than drawn separately. Some stress-dependent or non-canonically translated proteins, such as ATF4 via uORF/reinitiation and proposed HIF-1α or c-MYC IRES-like routes, are themselves TFs.
SCRIBE Pol II + pausing RNA polymerase II is a ~550 kDa, 12-subunit enzyme. Its CTD tail (YSPTSPS repeats) is a signaling hub: Ser5-P marks initiation/capping, Ser2-P elongation, and Ser7-P non-coding RNA programs. Promoter-proximal pausing stalls Pol II 25-50 bp after the TSS through NELF and DSIF. P-TEFb release enables productive elongation. SETD2 and METTL3/14 are recruited through Pol II, coupling elongation to H3K36me3 and m6A deposition.

Layer 3 — Co-Transcriptional Processing

Nascent RNA processing coupled to Pol II progression.

Code name Full name Exact definition
SHIELD 5’ capping Addition of an m7G cap to the 5’ end of nascent RNA at ~25-30 nt, coupled to Ser5-P CTD. The cap protects against 5’→3’ exonucleases and is recognized by eIF4E for translation and CBC for nuclear export.
SPLICER Alternative splicing Intron excision and exon joining by the spliceosome (U1/U2/U4/U6/U5 snRNPs plus many proteins). Most multi-exon human genes produce multiple isoforms. Regulation occurs through exon skipping, intron retention, alternative splice sites, and mutually exclusive exons. Pol II elongation speed creates a kinetic window for weak exon recognition, and histone marks such as H3K36me3 recruit splicing regulators.
TRIMMER Alternative polyadenylation (APA) Many mammalian genes have multiple cleavage/polyadenylation sites, producing isoforms with different 3’UTR lengths. CPA factors recognize the AAUAAA signal upstream of the polyA site. Long 3’UTRs expose additional miRNA and RBP sites, increasing post-transcriptional regulation.
RECODER A-to-I editing (ADAR) ADAR enzymes deaminate adenosine to inosine in dsRNA. Inosine is read as guanosine, recoding RNA information. ADAR1 p150 is interferon-induced and marks endogenous Alu dsRNAs as self; ADAR2 specializes in nuclear neuronal recoding. A-to-I editing near splice sites can prevent Alu exonization and downstream NMD.

Layer 4 — Post-Transcriptional Control

Regulation of mature mRNAs in the nucleus and cytoplasm.

Code name Full name Exact definition
STAMP m6A epitranscriptome N6-methyladenosine (m6A) is an abundant mRNA modification enriched near stop codons, long exons, and some 5’UTRs. Writers: METTL3/14/WTAP. Erasers: FTO, ALKBH5. Readers: YTHDF1/2/3 and YTHDC1. The classic model links YTHDF1 to translation, YTHDF2 to decay, YTHDF3 to output coordination, and YTHDC1 to splicing/export, but recent work also emphasizes partial redundancy among cytoplasmic YTHDF proteins. Other RNA modifications such as pseudouridine, m5C, m1A, ac4C, and 2’-O-methylation are treated as related epitranscriptomic extensions rather than separate boxes in v7.
READERS Regulatory RBPs Roughly 1500 human RNA-binding proteins use RRM, KH, CCCH zinc finger, PAZ, DEAD-box, and other modules. They regulate splicing, stability, translation, localization, and IRES activity. Examples include SRSF proteins, hnRNPs, HuR/ELAVL1, TTP/ZFP36, FMRP, Staufen1, PTB, DAP5/eIF4G2, and hnRNPQ.
DARTS miRNA-RISC ~22 nt microRNAs are processed by Drosha/DGCR8, Exportin-5, Dicer/TRBP, and AGO2 loading. Imperfect seed pairing to 3’UTRs recruits TNRC6/CCR4-NOT, causing deadenylation, decapping, and translational repression.
SPONGE Cytoplasmic lncRNAs Cytoplasmic lncRNAs can act as ceRNAs or miRNA sponges, but only when target-site abundance, affinity, and colocalization support meaningful competition. Examples include CDR1as/miR-7, HULC, and cytoplasmic HOTAIR contexts. Other lncRNAs modulate translation or act as decoys.
CENSOR NMD (nonsense-mediated mRNA decay) Surveillance of mRNAs carrying premature stop codons. If translation terminates >50-55 nt upstream of an exon junction complex, UPF factors and SMG1 trigger rapid degradation. NMD also regulates physiological alternative splicing products.
TIMER mRNA stability / decay mRNA half-lives range from minutes to over a day. The main route is deadenylation by CCR4-NOT/PAN2-PAN3, decapping by DCP1/2, and 5’→3’ decay by XRN1; the exosome provides 3’→5’ decay. ARE-binding proteins, miRNAs, and m6A tune stability.
CLIPS RNA G-quadruplexes (rG4) Guanine-rich RNA structures stabilized by K+ that occur in 5’UTRs, 3’UTRs, Pol II pause regions, and telomeric contexts. They can block 43S scanning, modulate IRES accessibility, and be unwound by helicases such as DHX36, eIF4A, and RHAU.
VAULT Stress granules / P-bodies Cytoplasmic RNA-protein condensates for mRNA storage, repression, or decay. Stress granules contain G3BP1, TIA-1, PABPC, and untranslated mRNAs. P-bodies contain DCP1/2, XRN1, CNOT, and decay machinery. Material exchanges dynamically between them.

Layer 5 — Translation

Protein synthesis control at the ribosome.

Code name Full name Exact definition
FORGE mTOR → cap-dependent initiation mTORC1 phosphorylates 4E-BP1, releasing eIF4E and enabling eIF4F assembly. eIF4F recruits the 43S PIC, scans the 5’UTR, and recognizes AUG in a Kozak context. Insulin/nutrients activate PI3K/AKT/mTORC1, while AMPK inhibits mTORC1.
BRAKE ISR / eIF2α-P The integrated stress response uses GCN2, PERK, HRI, and PKR to phosphorylate eIF2α Ser51. eIF2α-P sequesters eIF2B, lowers ternary complex, and represses global cap-dependent translation while selectively favoring mRNAs such as ATF4 through uORF/reinitiation logic.
DECOY uORFs (upstream ORFs) Upstream ORFs in 5’UTRs divert scanning ribosomes and usually reduce main ORF translation. Short uORFs can permit reinitiation, and under stress ATF4 is selectively translated because low ternary complex causes bypass of inhibitory downstream uORFs.
BYPASS IRES (Internal Ribosome Entry Sites) RNA elements that recruit ribosomes through routes less dependent on the cap. Viral IRESs are well established; many cellular IRES claims remain context-dependent because bicistronic assays can confound cryptic promoters, splicing, or readthrough. Proposed cellular examples include HIF-1α, VEGF-A, FGF2, p53 isoforms, and c-MYC; ATF4 is mainly uORF/reinitiation-driven.
TEMPO Codon usage + tRNA modifications + ribosome heterogeneity Synonymous codons translate at different speeds depending on cognate tRNA abundance. tRNA modifications affect decoding fidelity, frameshifting, and stalling. Ribosomal protein variation or rRNA modifications may bias translation in some contexts, but “specialized ribosomes” remain experimentally difficult and should be treated as contextual rather than a settled general code. TEMPO is not autonomous: tRNA abundance, ribosome biogenesis, and rRNA/ribosome state are shaped by growth programs such as MYC/mTOR/Pol I/Pol III, while initiation load and stress change ribosome density and elongation context. Decoding fidelity (merged-in DECODE concept): TEMPO also covers programmed deviations from the genetic code at the ribosome. Deep proteogenomics across >1,000 human samples (6 cancers, 26 healthy tissues) identified ~8,746 unique amino-acid substitutions in 1,767 genes arising from alternate ribosomal decoding — not explained by genomic variants and not A-to-I editing — yielding proteoforms that are stable, abundant, and tissue/cancer-specific (Tsour et al., Nature 2026). Mechanistically this is the fidelity face of the same tRNA/codon/elongation axis (near-cognate decoding under tRNA-supply and tempo constraints), distinct from RECODER (transcript-level A-to-I) and from INSPECTOR (which removes aberrant products — here a fraction instead escapes QC and persists into MATURE). Treat the substituted-proteoform output as contextual and still being mapped, not a settled quantitative rule.
INSPECTOR Translation surveillance (RQC/NGD/NSD) Quality-control mechanisms detect defective mRNAs and peptides. NGD responds to stalled ribosomes, NSD to mRNAs lacking stop codons, and RQC to stuck ribosomes whose nascent chains are ubiquitinated by LTN1. NEMF CAT-tailing can mark stalled peptides for degradation.

Layer 6 — Post-Translational Regulation

Protein modification, maturation, routing, and destruction after synthesis.

Code name Full name Exact definition
SWITCH Phosphorylation / O-GlcNAcylation Phosphorylation on Ser/Thr/Tyr changes conformation, interaction sites, and enzyme or TF activity. It is reversible through phosphatases. O-GlcNAcylation adds GlcNAc on Ser/Thr and can crosstalk with phosphorylation. These switches activate kinases, Pol II CTD regulators, ISR kinases, and DDR pathways.
ROUTER Ubiquitin code The E1-E2-E3 cascade conjugates ubiquitin to substrate Lys residues. Chain topology determines fate: K48 often routes to proteasome, K63 supports signaling/scaffolding/autophagy routing, K11 marks mitotic degradation, and M1/linear supports NF-κB signaling.
TETHER SUMOylation SUMO1/2/3 are conjugated by SAE1/SAE2, UBC9, and PIAS-family E3s. SUMOylation changes protein-protein interactions, stabilizes nuclear complexes, recruits co-repressors, modulates DNA repair, and can bridge to ROUTER through STUbL E3 ligases such as RNF4/RNF111.
LICENSE Neddylation / CRL activation NEDD8 is a ubiquitin-like protein conjugated mainly to cullins. Neddylation activates Cullin-RING ligases by improving substrate/E2 positioning. It is not an autonomous degradation route but an upstream switch that licenses ROUTER capacity for specific substrates. CRL licensing is itself regulated by assembly state, substrate-adaptor availability, CAND1/CSN cycles, and signaling context.
DESTROY Protein destruction: proteasome + selective autophagy A fused box for the two major protein-clearance outputs. The 26S proteasome reads mostly K48-polyUb, deubiquitinates, unfolds, and degrades short-lived or damaged proteins. Selective autophagy uses receptors such as p62/SQSTM1 to link ubiquitinated cargo to LC3/GABARAP and lysosomes, especially for aggregates, organelles, or bulky cargo.
MATURE Chaperones / UPR Chaperones such as Hsp70/Hsc70, Hsp90, and CCT/TRiC fold, refold, or triage proteins. CHIP links chaperones to ubiquitination of misfolded substrates. The ER UPR uses PERK, IRE1, and ATF6 to slow translation, expand folding capacity, and induce ER chaperone programs.
PAR ADP-ribosylation / PARP / PAR PARP1 detects DNA breaks and synthesizes poly-ADP-ribose on itself and other proteins. PAR chains nucleate DNA-damage condensates and recruit repair factors such as FUS, XRCC1, and RPA. PAR can also recruit ubiquitin/E3 factors and couple repair, remodeling, and local turnover, but broad proteasomal destruction is context-dependent.

Cross-Cutting Meta-Principles

Code name Full name Exact definition
LLPS Liquid-liquid phase separation A thermodynamic process in which macromolecules concentrate into a dense phase or condensate-like assembly. Driven by multivalent interactions among IDRs, RGG repeats, tyrosines, RNA, and RNA-binding proteins. LLPS is not a single regulatory mechanism but a physical principle used by stress granules, P-bodies, PAR-damage foci, some transcriptional condensates, and some polyUb/proteolytic condensates.
DECAY Turnover / clearance A functional output that removes a molecule from the system: mRNA decay through TIMER/CENSOR, protein destruction through DESTROY, and broader switches between temporary storage and elimination.

II. Relation Catalogue (89 Mechanism Edges + 7 Meta Annotations)

Color Code

| Color | Type | Meaning | |——-|——|———| | Green #27ae60 | Direct activation | A recruits, activates, or deposits B. | | Red #c0392b | Direct repression | A blocks or prevents B (arrowhead=tee). | | Yellow #f4d03f | Pol II coupling | Mechanism linked to Pol II progression. | | Orange #e67e22 | Co-transcriptional coupling | Regulation coupled to transcription. | | Purple #8e44ad | Post-transcriptional / m6A / RBP | Post-transcriptional regulation. | | Gray #566573 | PTM / post-translational signaling | Post-translational regulation. | | Blue #2e86c1 | Structural / 3D | Three-dimensional organization. | | Cyan #22d3ee dotted border | LLPS | Participation in LLPS/condensate logic. | | Pink #f472b6 dashed border | DECAY | Participation in turnover/clearance logic. |

All Relations By Source Layer

3D → 3D

| Source | Target | Relation name | Mechanism | |——–|——–|—————|———–| | ZONES | FENCES | CONTAINS | A/B compartments and TADs coexist and influence each other, but compartments do not simply create TADs. | | ZONES | WRITER-R | ANCHORS-B | B compartments anchor at the lamina and co-localize with H3K9/27me3. | | FENCES | BRIDGES | BIASES/INSULATES | TAD boundaries probabilistically constrain enhancer-promoter contacts; they bias and insulate rather than absolutely delimit all loops. | | BRIDGES | HUBS | SUPPORTS-SE-CONTACTS | Enhancer-promoter contacts can support super-enhancer function, but super-enhancers are not simply anchored by individual loops. |

3D → Epigenetics

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | OPENER | HUBS | H3K27AC-BRD4 | BRD4 reads H3K27ac through bromodomains, supporting enhancer hubs. | | HUBS | OPENER | SE-ACETYLATION | Super-enhancers maintain a highly acetylated local state. |

Epigenetics → Epigenetics

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | SILENCER | WRITER-R | CO-RECRUIT (bidirectional) | MBD recruits SUV39H1 to H3K9me3, and HP1 can recruit DNMT3. | | OPENER | SHUFFLER | ACETYL-REMODEL | Acetylated marks recruit bromodomain readers and remodelers such as SWI/SNF/BAF. | | GUIDES | SILENCER | PIRNAGUIDE | piRNA-PIWI guides DNMT3L/3A toward transposons for de novo methylation. | | GUIDES | WRITER-R | LNCRNA-POLYCOMB | XIST and some nuclear lncRNA contexts recruit or organize Polycomb/repressive histone systems; specificity is context-dependent. |

Epigenetics → Transcription

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | OPENER | KEYS | OPENS-TF | Histone acetylation loosens nucleosomes and gives TFs access. | | WRITER-R | KEYS | SILENCES-TF ⊣ | H3K27me3/H3K9me3 compact chromatin and exclude TFs. | | SHUFFLER | KEYS | REMODELS | CRCs reposition or evict nucleosomes to create TF binding windows. | | WRITER-A | SCRIBE | RECRUITS-POL2 | H3K4me3 recruits TAF3/TFIID and supports Pol II recruitment. | | HUBS | SCRIBE | RELEASES-PAUSE | P-TEFb concentrated in SEs phosphorylates Ser2-CTD and releases paused Pol II. | | OPENER | ZONES | ACETYL-TO-A | H3K27ac and active chromatin favor A-compartment identity. | | WRITER-R | ZONES | REPRESS-TO-B | H3K27me3/H3K9me3 and heterochromatin favor B-compartment identity. | | SILENCER | ZONES | METH-TO-B | CpG methylation recruits MBD, compacts chromatin, and favors B compartments. |

Transcription → Epigenetics (feedbacks)

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | KEYS | OPENER | TF-HAT | Activating TFs recruit p300/CBP to deposit H3K27ac. | | KEYS | WRITER-A | TF-KMT | TFs recruit MLL/KMT2 enzymes to deposit H3K4me3. | | KEYS | SHUFFLER | TF-CRC (back) | TFs recruit SWI/SNF to their target genes. | | KEYS | GUIDES | TF-NCRNA-EPI | TFs can activate piRNA/lncRNA loci that later guide chromatin complexes. | | KEYS | SPONGE | TF-LNCRNA | TFs activate cytoplasmic lncRNA loci, adding a post-transcriptional output. |

Transcription → Transcription

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | KEYS | SCRIBE | INITIATES | TFs recruit Mediator, assemble the PIC, and recruit Pol II. | | KEYS | HUBS | DEFINES-SE | Master TFs such as OCT4, MYC, and SOX2 define and maintain SE identity. | | KEYS | RECODER | IFN-ADAR | IFN-response TFs such as IRF3/7 transcribe ADAR1p150. |

Transcription → Translation

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | KEYS | TEMPO | GROWTH-DECODING-BUDGET | MYC and other growth-state TF programs regulate ribosome-biogenesis, Pol I/Pol III, tRNA, and translation-capacity genes, indirectly shaping the decoding budget represented by TEMPO. |

Transcription → Co-Transcriptional

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | SCRIBE | SHIELD | CTD-CAP | Ser5-P CTD recruits capping enzymes. | | SCRIBE | SPLICER | RATE-SPLICE () | Pol II elongation speed sets the opportunity window for weak exon inclusion. | | SCRIBE | TRIMMER | **CTD-CST | Pol II Ser2-P recruits CstF for cleavage and polyadenylation. | | SCRIBE | STAMP | CTD-M6A | METTL3/14 is recruited by the CTD for co-transcriptional m6A. | | SCRIBE | ZONES | TXN-TO-A | Transcriptional activity helps maintain active regions in A compartments. | | WRITER-A | SPLICER | HISTONE-SPLICE () | H3K36me3 deposited by SETD2-associated Pol II recruits MRG15/PTB to affect exon inclusion. | | SCRIBE | WRITER-A | **SETD2-COUPLING (**) | SETD2 physically couples to Pol II Ser2-P and deposits H3K36me3 during elongation. |

(**) = key kinetic couplings linked to principle C.

Post-Transcriptional → Co-Transcriptional (feedbacks)

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | STAMP | SPLICER | M6A-SPLICE (back) | Nuclear YTHDC1 binds m6A and recruits SRSF3/SRSF10 to affect splicing. | | READERS | SPLICER | RBP-SPLICE (back) | SR proteins and hnRNPs regulate spliceosomal ESE/ESS recognition. | | RECODER | SPLICER | ADAR-SPLICE (bidirectional) | ADAR1/2 edit 5’ splice sites and alter U1 snRNA recognition. |

Co-Transcriptional → Post-Transcriptional

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | SPLICER | CENSOR | SPLICE-NMD | Alternative exons introducing PTCs send the isoform to NMD. | | TRIMMER | DARTS | APA-MIRNA | Long 3’UTRs expose additional miRNA sites. | | TRIMMER | READERS | APA-RBP | Long 3’UTRs expose additional RBP sites. | | RECODER | CENSOR | ADAR-NMD | Alu exonization can create PTCs; ADAR editing near 5’SS can prevent exonization. |

Post-Transcriptional Intra-Layer

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | STAMP | TIMER | M6A-DECAY | m6A can promote decay through reader context, but YTHDF redundancy and transcript context make this a contextual rather than one-reader-one-output edge. | | STAMP | CLIPS | M6A-G4 | m6A can destabilize adjacent RNA G-quadruplex structures. | | DARTS | TIMER | MIRNA-DECAY | AGO2-RISC recruits CCR4-NOT for deadenylation and decapping. | | SPONGE | DARTS | CERNA ⊣ | lncRNA/circRNA ceRNAs can sponge miRNAs when stoichiometry and colocalization are sufficient. | | CENSOR | TIMER | NMD-DECAY | UPF1-P recruits SMG6 and SMG5/7 for rapid degradation. | | TIMER | VAULT | MRNA-SG (bidirectional/contextual) | Untranslated mRNAs can enter granules and later return to translation or decay; granule localization alone is not proof of degradation. | | READERS | TIMER | RBP-STABILITY | HuR/ELAVL1 stabilizes AREs, while TTP/ZFP36 destabilizes through CCR4-NOT. | | READERS | TRIMMER | RBP-APA | RBPs regulate cleavage/polyadenylation and alternative polyA-site choice in many contexts. | | READERS | VAULT | RBP-GRANULES | RBPs help partition mRNPs into stress granules, P-bodies, or other RNP assemblies. | | CLIPS | BYPASS | G4-IRES | rG4 structures in 5’UTRs can modulate IRES accessibility. |

Post-Transcriptional → Translational

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | STAMP | FORGE | M6A-INIT | m6A can stimulate initiation through reader/context-dependent mechanisms, but this should not be read as a universal YTHDF1 activation arrow. | | STAMP | BYPASS | M6A-NONCANONICAL | 5’UTR m6A can support noncanonical initiation in selected contexts; evidence is transcript- and assay-dependent. | | READERS | FORGE | FMRP-REPRESS ⊣ | FMRP binds polysomes and represses translation. | | DARTS | FORGE | MIRNA-TRANSL ⊣ | miRNAs can repress translation, but mammalian miRNA effects often proceed through deadenylation and decay; direct translational repression is context-dependent. | | CLIPS | FORGE | G4-BLOCK ⊣ | 5’UTR rG4 blocks 43S scanning. |

Capping → Translation

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | SHIELD | FORGE | CAP-EIF4E | The m7G cap is recognized by eIF4E, enabling eIF4F assembly and initiation. | | SHIELD | TIMER | CAP-PROTECTS | The cap protects mRNAs from 5’ decay; decapping commits many transcripts to XRN1-mediated turnover. |

Translational Intra-Layer

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | BRAKE | DECOY | ISR-UORF () | eIF2α-P limits ternary complex, causing ribosomes to bypass inhibitory uORFs and induce ATF4. | | BRAKE | BYPASS | **ISR-NONCANONICAL | Stress can favor selected noncanonical initiation routes, but stress does not generally activate all IRES-like translation; ATF4 is mainly uORF/reinitiation-driven. | | BRAKE | TEMPO | STRESS-DECODING-CONTEXT | ISR/stress lowers initiation flux and changes ribosome loading, making elongation-speed and codon/tRNA constraints matter in a different context. | | DECOY | FORGE | UORF-COMPETE ⊣ | uORFs sequester ribosomes and reduce main ORF translation. | | FORGE | INSPECTOR | TRANSLATION-EXPOSES-STALLS | Translation exposes ribosomes to stall risk; stalls or defective elongation, not initiation itself, trigger NGD/NSD/RQC. | | FORGE | TEMPO | INITIATION-LOAD | Cap-dependent initiation rate sets ribosome density on transcripts; higher loading can expose elongation bottlenecks, collisions, or codon/tRNA constraints. | | TEMPO | INSPECTOR | CODON-STALL | Rare codons can prolong ribosome pauses and trigger NGD/NSD/RQC. | | TEMPO | TIMER | CODON-STABILITY | Codon optimality and translation elongation can affect mRNA stability through ribosome-speed-dependent decay pathways. | | TEMPO | MATURE | COTRANSL-FOLD | Translation rhythm shapes co-translational folding kinetics. | | INSPECTOR | TIMER | NGD-NSD-DECAY | NGD and NSD surveillance produce mRNA decay outputs, not only nascent-chain destruction. | | INSPECTOR | DESTROY | RQC-26S | CAT-tailed stalled nascent peptides are recognized by LTN1 and degraded. |

Translation → Post-Translational

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | FORGE | MATURE | COTRANSL-MATURATION | Nascent translation exposes chains to co-translational chaperones and folding. | | FORGE | SWITCH | MTOR-GROWTH-FEEDBACK | Translation/growth signaling is coupled mainly through mTORC1 outputs such as S6K and 4E-BP; AKT is usually upstream of mTORC1 rather than a simple downstream output. |

Post-Translational Intra-Layer

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | SWITCH | ROUTER | SWITCH-DEGRON | Phospho-degrons are recognized by SCF E3s such as β-TrCP/Fbxw7 or APC/C. | | SWITCH | TETHER | PDSM | PDSM motifs use Ser phosphorylation to activate SUMOylation on nearby Lys. | | ROUTER | DESTROY | ROUTER-DESTROY | K48-polyUb routes to 26S proteasome; K63-polyUb can recruit p62/SQSTM1 for selective autophagy. | | TETHER | ROUTER | STUBLS | polySUMO is recognized by RNF4/RNF111 STUbL E3s and converted into ubiquitin routing. | | LICENSE | ROUTER | CRL-ACTIVATION | Cullin neddylation activates CRL E3 ligases for substrate ubiquitination. | | SWITCH | LICENSE | SIGNAL-CRL-LICENSE | Kinase/signaling context can regulate CRL substrate receptors, substrate engagement, CAND1 exchange, CSN deneddylation balance, and therefore effective CRL licensing. | | PAR | ROUTER | PAR-UB-REPAIR | PAR-dependent repair assemblies can recruit ubiquitin/E3 factors and local turnover machinery in context; broad PAR→proteolytic-condensate destruction is too strong. | | MATURE | BRAKE | UPR-ISR | PERK in the UPR phosphorylates eIF2α and activates the ISR. | | DESTROY | FORGE | LYSOSOME-MTOR | Amino acids released by lysosomes activate Ragulator/RRAG and reactivate mTORC1. | | DESTROY | KEYS | DESTROY-TF | Degradation of TF inhibitors, such as IκBα, activates TF programs such as NF-κB. |

Post-Translational → Transcription / Pol II

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | SWITCH | SCRIBE | CDK9-CTD | Activated CDK9/P-TEFb phosphorylates Ser2-CTD and releases paused Pol II. | | SWITCH | BRAKE | KINASE-EIF2A | GCN2, PERK, HRI, and PKR phosphorylate eIF2α Ser51 and activate BRAKE. | | SWITCH | KEYS | SWITCH-TF | Phosphorylation changes TF activity, localization, stability, or interaction partners. | | SWITCH | PAR | DDR-PARP | DDR kinase context modulates PARP1 activation and PAR-dependent repair assemblies. | | ROUTER | KEYS | UB-SIGNAL-TF | K63/M1 ubiquitin scaffolds activate signaling routes such as NF-κB without necessarily destroying the TF. | | ROUTER | MATURE | UB-CHAPERONE | Ubiquitin tags and chaperone systems are coupled during proteostasis and substrate triage. | | MATURE | ROUTER | CHAPERONE-UB | CHIP, ERAD, and other chaperone-triage systems connect misfolded or immature proteins to ubiquitin routing. | | MATURE | DESTROY | TRIAGE-DESTROY | Chaperone triage sends persistently misfolded proteins toward proteasomal or autophagic clearance. |

Cross-Cutting Meta-Principles

| Source | Target | Name | Mechanism | |——–|——–|——|———–| | LLPS | HUBS | LLPS-SE | LLPS/transcriptional condensates can contribute to super-enhancer activity without being identical to it. | | LLPS | VAULT | LLPS-SG-PB | LLPS forms stress granules and P-bodies. | | LLPS | DESTROY | LLPS-DESTROY | LLPS can form proteolytic or polyUb condensates in some contexts, but not all proteasomal or autophagic degradation is condensate-based. | | LLPS | PAR | LLPS-PAR | PAR chains nucleate DNA-repair condensates. | | DECAY | TIMER | DECAY-MRNA | mRNA turnover through deadenylation, decapping, and exonucleases. | | DECAY | CENSOR | DECAY-NMD | NMD as a surveillance and elimination branch for aberrant mRNAs. | | DECAY | DESTROY | DECAY-DESTROY | Ubiquitin-dependent protein degradation or selective lysosomal clearance of proteins, aggregates, or organelles. |

III. Overlaps And Mergers — What Was Consolidated

Merged entities Rationale
Super-enhancers + transcriptional condensates Kept fused in the main graph for compactness but strongly caveated: super-enhancer is a genomic/ChIP-seq enhancer-cluster definition; condensate is a dynamic physical assembly enriched in coactivators and requires direct biophysical evidence.
A/B compartments + global epigenetic state Strongly correlated; compartments emerge from marks but are not identical to them.
YTHDF1 + YTHDF2 + YTHDF3 → STAMP One signal, m6A, with partly specialized but also redundant readers depending on context.
Codon usage + tRNA modifications + ribosome heterogeneity → TEMPO Three facets of decoding-efficiency control.
SWI/SNF + ISWI + CHD + INO80 → SHUFFLER Same ATP-dependent remodeling principle across four subfamilies.
eRNAs (enhancer RNAs) Mostly enhancer-activity readouts, not a separate mechanism box here.
ISR branch PERK / UPR PERK is both an ISR kinase and a UPR branch, integrated through MATURE → BRAKE.
siRNA / miRNA Share RISC/AGO2; animal siRNA is mostly an experimental/tool-like variant here, folded into DARTS.
ceRNA hypothesis Special case of SPONGE + DARTS, kept as a skeptical/conditional mechanism requiring abundance, affinity, localization, and loss-of-function stoichiometric support.

Appendix A — Databases And Resources

Resource URL Contents
ENCODE https://encodeproject.org ChIP-seq, ATAC-seq, CTCF, histone marks, 150+ cell types
Roadmap Epigenomics https://egg2.wustl.edu/roadmap 127 cell types, methylation + histone maps
GTEx https://gtexportal.org Tissue-specific eQTLs
FANTOM5 https://fantom.gsc.riken.jp/5 TSS atlas, eRNAs, lncRNAs
miRBase https://mirbase.org miRNA catalogue
POSTAR3 http://postar.ncrnalab.org RBP binding sites from CLIP-seq
RMBase v3 https://rmbase.sysu.edu.cn RNA modification sites (m6A, m5C, Ψ…)
G4 motif resources To verify G-quadruplexes in transcriptomes
PhosphoSitePlus https://phosphosite.org PTM sites (phosphorylation, ubiquitination, acetylation, methylation)
STRING https://string-db.org Protein-protein interactions
UniProt https://uniprot.org Protein annotations + PTMs

Appendix B — Foundational References

v7 — 37 mechanisms, 2 meta-principles, 89 mechanism relations + 7 meta annotations File: assets/documents/gene-regulation-landscape-details.md Diagram: assets/documents/gene-reg-v7.dot + assets/images/gene-reg-v7.png