Pathway Human Homo sapiens

Epigenetic regulation of gene expression

R-HSA-212165 in Reactome release 97: under Gene expression (Transcription), with 325 genes placed in it by the mapping files and 7 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-212165 (mouse), R-RNO-212165 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-212165.7
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2014-03-12
Last updated: 2023-03-29
Events inside: 7, counted from the record

Epigenetic processes regulate gene expression by modulating the frequency, rate, or extent of gene expression in a mitotically or meiotically heritable way that does not entail a change in the DNA sequence. Originally the definition applied only to heritability across generations but later also encompassed the heritable changes that occur during cellular differentiation within one organism.

Molecular analysis shows epigenetic changes comprise covalent modifications, such as methylation and acetylation, to DNA and histones. RNA interference has been implicated in the initiation of some epigenetic changes, for example transcriptional silencing of transposons. Proteins which bind to the modified DNA and histones are then responsible for repressing transcription and for maintaining the epigenetic modifications during cell division.

During differentiation, patterns of gene expression are established by polycomb complexes PRC1 and PRC2. PRC2 methylates histones and DNA to produce the initial marks of repression: trimethylated lysine-27 on histone H3 (H3K27me3) and 5-methylcytosine in DNA. PRC2, through its component EZH2 or, in some complexes, EZH1 trimethylates lysine-27 of histone H3. The H3K27me3 produced by PRC2 is bound by the Polycomb subunit of PRC1. PRC1 ubiquitinates histone H2A and maintains repression.

PRC2 and other epigenetic systems modulate gene expression through DNA methyation, the transfer of a methyl group from S-adenosylmethionine to the 5 position of cytosine in DNA by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3A, and DNMT3B.

In the reverse process TET1,2,3 and TDG demethylate DNA through the oxidation of the methyl group of 5-methylcytosine by TET enzymes and the excision of the oxidized product (5-formylcytosine or 5-carboxylcytosine) by TDG.

Ribosomal RNA (rRNA) genes are activated and deactivated according to the metabolic requirements of the cell. Positive epigenetic regulation of rRNA expression occurs through chromatin modifications produced by activators such as ERCC6 (CSB), the B-WICH complex, and histone acetylases such as KAT2B (PCAF). Negative epigenetic regulation of rRNA expression occurs through chromatin modifications produced by repressors such as the eNoSC complex, SIRT1, and the NoRC complex.

WDR5 is a component of six histone methyltransferases and three histone acetyltransferases involved in epigenetic regulation of gene expression (reviewed in Guarnaccia and Tansey 2018).

Endogenous retroelements are transposable elements that transpose to new genomic locations via an RNA intermediate and reverse transcription. Retroelements are silenced epigenetically in the human genome by mechanisms that include PIWI-interacting small RNAs (piRNAs) that transcriptionally silence retroelements through an RNA interference mechanism, KRAB-ZFP zinc finger-type repressors that bind specific DNA sequences in retroelements, and the HUSH complex that recognizes retroelements through nascent RNA or through existing histone H3 lysine-9 trimethylation (Almeida et al. 2022).

Literature Reactome attaches

Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signalsNat. Genet., 2003, vol. 33, p. 245-54PubMed 12610534
Moonlighting with WDR5: A Cellular MultitaskerJ Clin Med, 2018, vol. 7PubMed 29385767
Taming transposable elements in vertebrates: from epigenetic silencing to domesticationTrends Genet, 2022, vol. 38, p. 529-553PubMed 35307201

Reactome's record lists 14 orthologous events, R-MMU-212165 (Mus musculus), R-RNO-212165 (Rattus norvegicus) among the species this site serves, and 12 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-05 ET · Reactome pathway browser"Epigenetic regulation of gene expression". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-212165 with StableID: R-HSA-212165.7 (accessed 2026-10-05 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 325 genes in this human pathway; showing 301 to 325, in pages of 100, sorted by symbol for reading. The order carries no ranking. 4 of the rows shown carry an id the identity file does not name, kept as the source wrote it.

Genes Reactome places in this human pathway, page 4 of 4
Gene	Authority id	Mapping file id	Evidence codes
GeneZNF324	AuthorityHGNC:14096	Mapping file id25799 NCBI file	EvidenceIEA, TAS
GeneZNF331	AuthorityHGNC:15489	Mapping file id55422 NCBI file	EvidenceIEA, TAS
GeneZNF33A	AuthorityHGNC:13096	Mapping file id7581 NCBI file	EvidenceIEA, TAS
GeneZNF354A	AuthorityHGNC:11628	Mapping file id6940 NCBI file	EvidenceIEA, TAS
GeneZNF382	AuthorityHGNC:17409	Mapping file id84911 NCBI file	EvidenceIEA, TAS
GeneZNF418	AuthorityHGNC:20647	Mapping file id147686 NCBI file	EvidenceIEA, TAS
GeneZNF425	AuthorityHGNC:20690	Mapping file id155054 NCBI file	EvidenceIEA, TAS
GeneZNF454	AuthorityHGNC:21200	Mapping file id285676 NCBI file	EvidenceIEA, TAS
GeneZNF519	AuthorityHGNC:30574	Mapping file id162655 NCBI file	EvidenceIEA, TAS
GeneZNF534	AuthorityHGNC:26337	Mapping file id147658 NCBI file	EvidenceIEA, TAS
GeneZNF547	AuthorityHGNC:26432	Mapping file id284306 NCBI file	EvidenceIEA, TAS
GeneZNF610	AuthorityHGNC:26687	Mapping file id162963 NCBI file	EvidenceIEA, TAS
GeneZNF649	AuthorityHGNC:25741	Mapping file id65251 NCBI file	EvidenceIEA, TAS
GeneZNF669	AuthorityHGNC:25736	Mapping file id79862 NCBI file	EvidenceIEA, TAS
GeneZNF680	AuthorityHGNC:26897	Mapping file id340252 NCBI file	EvidenceIEA, TAS
GeneZNF708	AuthorityHGNC:12945	Mapping file id7562 NCBI file	EvidenceIEA, TAS
GeneZNF765	AuthorityHGNC:25092	Mapping file id91661 NCBI file	EvidenceIEA, TAS
GeneZNF778	AuthorityHGNC:26479	Mapping file id197320 NCBI file	EvidenceIEA, TAS
GeneZNF816	AuthorityHGNC:26995	Mapping file id125893 NCBI file	EvidenceIEA, TAS
GeneZNF93	AuthorityHGNC:13169	Mapping file id81931 NCBI file	EvidenceIEA, TAS
GeneZZZ3	AuthorityHGNC:24523	Mapping file id26009 NCBI file	EvidenceTAS
Geneno symbol in the identity file	Authoritynone	Mapping file idKJ852773 as written	EvidenceIEA, TAS
Geneno symbol in the identity file	Authoritynone	Mapping file idNR_046235 as written	EvidenceIEA
Geneno symbol in the identity file	Authoritynone	Mapping file idU13369 as written	EvidenceIEA
Geneno symbol in the identity file	Authoritynone	Mapping file idX58075 as written	EvidenceIEA, TAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Gene expression (Transcription)R-HSA-741601,545 genes

Children

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.