Pathway Human Homo sapiens

Regulation of endogenous retroelements

R-HSA-9842860 in Reactome release 97: under Epigenetic regulation of gene expression, with 144 genes placed in it by the mapping files and 3 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-9842860 (mouse), R-RNO-9842860 (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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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-9842860.2
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2024-06-15
Events inside: 3, counted from the record

Transposable elements (TEs) constitute about 48.34% of the human genome (Osmanski et al. 2023) and can be classified by their transposition mechanisms: DNA transposons (about 3% of the human genome) transpose by excising a DNA intermediate and inserting it into a new location; retrotransposons (about 33% of the human genome) transpose by transcribing an element, reverse transcribing the RNA to DNA, and inserting the DNA copy into a new location.

Retrotransposons can be divided into those that contain long terminal repeats (LTRs) and those that lack LTRs. Retrotransposons that contain LTRs are believed to be remnants of retroviruses, are therefore called endogenous retroviruses, and constitute about 9.45% of the human genome (Lander et al. 2001, Osmanski et al. 2023). No endogenous retroviruses are known to be currently transpositionally active in humans, with the most recent transpositions estimated to have occurred about 0.67 million years ago (Wildschutte et al. 2016).

Retrotransposons that lack LTRs constitute about 34% of the human genome and mostly have uncertain origins: Long interspersed nuclear elements (LINEs, about 18,99% of the genome) encode two proteins, an RNA-binding protein (ORF1p) and a reverse transcriptase/endonuclease (ORF2p), that confer autonomous transposition activity; short interspersed nuclear elements (SINEs, about 14.66% of the genome) do not encode proteins and require proteins produced in trans by LINEs for transposition (Lander et al. 2001). Of the 3 families of LINEs, only the LINE1 family is known to be currently active (Lander et al. 2001, Beck et al. 2010). Of the SINEs, only Alu elements, which evolved from the 7SL RNA of the signal recognition particle, are known to be currently active (Lander et al. 2001, Bennett et al. 2008).

Surprisingly, although retroelements can cause deleterious mutations due to insertions and recombination, their genomic elements and expression are required for embryogenesis. The envelope proteins ERVW-1 (Syncytin-1) of the HERV-W endogenous retrovirus and ERVFRD-1 (Syncytin-2) of the HERV-FRD endogenous retrovirus act to fuse cells in the trophoblast (reviewed in Gholami Barzoki et al. 2023). TEs contain binding sites for pluripotency factors (for example OCT4, SOX2, and NANOG) as well as cell lineage-specific factors (Pontis et al. 2022), In humans, a hominid-specific TE family, LTR5Hs, become transcriptionally active during specification of primordial germ cells (PGCs) and serve to bind PGC transcription factors (Xiang et al. 2022). In mice, the retroviral MERVL element is transcribed in cleavage-stage embryos and during this time MERVL regulatory DNA elements activate expression of more than one hundred genes involved in zygotic genome activation (Macfarlan et al. 2012, Sakashita et al. 2023, Yang et al. 2024). In mouse embryos, transcripts from LINE1 retroelements are required to exit the 2-cell stage by serving as scaffolds for Nucleolin (NCL) and TRIM28 (KAP1) to repress Dux expression and activate rRNA expression (Percharde et al. 2018, Chen et al. 2021). LINE1 elements are also active in expressing cell type-specific transcripts in the developing and adult human brain (Garza et al. 2023). By binding transcription activators, retroelements such as LTR5 and LTR7 can also act as cis-regulatory networks in somatic cells (reviewed in Sundaram and Wysocka 2020, Low et al. 2021, Fueyo et al. 2022).

Retroelements are generally silenced transcriptionally by DNA methylation and histone modifications (reviewed in Geis and Goff 2020, Carotti et al. 2023, Stamidis and Zylicz 2023) or post-transcriptionally by RNA interference (reviewed in Geis and Goff 2020), however repressive chromatin marks are lost and retroelements are transcribed at two points during mammalian development: in early germ cells prior to meiosis and in zygotes immediately after fertilization (reviewed in Low et al. 2021). In germ cells, small RNAs of 24-31 nucleotides known as PIWI-interacting RNAs (piRNAs) are generated from transcripts of retroelements and, when bound to PIWI proteins, guide post-transcriptional decay of retroelement transcripts and re-impose chromatin modifications that repress transcription of retroelements.

Endogenous retroelements are also transcriptionally silenced by zinc finger-containing proteins, KRAB-ZFPs, that bind specific DNA sequences (reviewed in Yang et al. 2017). The human genome contains 423 KRAB-ZFP genes that encode 742 KRAB-ZFP proteins that appear to evolve in response to invasion by retroelements (reviewed in Huntley et al. 2006, Lupo et al. 2013). Specific KRAB-ZFPs bind specific families of retroelements and recruit the TRIM28 scaffold protein (also known as KAP1), which assembles a complex containing the histone methylase SETDB1 and the NuRD repressor complex to silence transcription of the retroelements (reviewed in Almeida et al. 2022).

The Human Silencing Hub (HUSH) complex directly binds RNA of LINE1 elements and trimethylates lysine-9 of histone H3 (H3K9) of nucleosomes assembled on the LINE1 that produced the RNA (reviewed in Seczynska and Lehner 2023). Trimethyl H3K9 (H3K9me3) is a repressive mark thus the result is de novo formation of heterochromatin at LINE1 elements. The HUSH complex also binds H3K9me3 and trimethylates H3K9 of adjacent nucleosomes, resulting in propagation of heterochromatin (reviewed in Seczynska and Lehner 2023).

In mice, N6 methylation of adenosine residues in RNAs can cause destabilization of the RNA (Chelmicki et al. 2021) and transcriptional silencing of the locus that produced the RNA (Xu et al. 2021, Liu et al. 2021). The effect of N6-methyladenosine on expression of human retroelements is less clear. Xiong et al. (2021) observed that N6-methyladenosine in transcripts of young LINE1 elements increased RNA expression while N6-methyladenosine in transcripts of ancient LINE1 elements decreased RNA expression. The mechanism responsible for the difference may involve the promotion of translation of young LINE1 elements by N6-methyladenosine residues located in the 5' untranslated region (Hwang et al. 2021).

Literature Reactome attaches

Transposable Elements: Epigenetic Silencing Mechanisms or Modulating Tools for Vertebrate Adaptations? Two Sides of the Same CoinInt J Mol Sci, 2023, vol. 24PubMed 37511347
Silencing and Transcriptional Regulation of Endogenous Retroviruses: An OverviewViruses, 2020, vol. 12PubMed 32823517
A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressorsGenome Res, 2006, vol. 16, p. 669-77PubMed 16606702
The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian EvolutionTrends Genet, 2017, vol. 33, p. 871-881PubMed 28935117
The sound of silence: mechanisms and implications of HUSH complex functionTrends Genet, 2023, vol. 39, p. 251-267PubMed 36754727
m<sup>6</sup>A RNA methylation regulates the fate of endogenous retrovirusesNature, 2021, vol. 591, p. 312-316PubMed 33442060
METTL3 regulates heterochromatin in mouse embryonic stem cellsNature, 2021, vol. 591, p. 317-321

Reactome's record lists 9 orthologous events, R-MMU-9842860 (Mus musculus), R-RNO-9842860 (Rattus norvegicus) among the species this site serves, and 7 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Regulation of endogenous retroelements". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9842860 with StableID: R-HSA-9842860.2 (accessed 2026-09-30 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 144 genes in this human pathway; showing 101 to 144, in pages of 100, sorted by symbol for reading. The order carries no ranking. 2 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 2 of 2
Gene	Authority id	Mapping file id	Evidence codes
GeneSMARCD1	AuthorityHGNC:11106	Mapping file id6602 NCBI file	EvidenceIEA
GeneSMARCD2	AuthorityHGNC:11107	Mapping file id6603 NCBI file	EvidenceIEA
GeneSMARCD3	AuthorityHGNC:11108	Mapping file id6604 NCBI file	EvidenceIEA
GeneSMARCE1	AuthorityHGNC:11109	Mapping file id6605 NCBI file	EvidenceIEA
GeneSPOCD1	AuthorityHGNC:26338	Mapping file id90853 NCBI file	EvidenceIEA
GeneSS18	AuthorityHGNC:11340	Mapping file id6760 NCBI file	EvidenceIEA
GeneSS18L1	AuthorityHGNC:15592	Mapping file id26039 NCBI file	EvidenceIEA
GeneSUMO2	AuthorityHGNC:11125	Mapping file id6613 NCBI file	EvidenceIEA
GeneTASOR	AuthorityHGNC:30314	Mapping file id23272 NCBI file	EvidenceIEA, TAS
GeneTRIM28	AuthorityHGNC:16384	Mapping file id10155 NCBI file	EvidenceIEA, TAS
GeneUBE2I	AuthorityHGNC:12485	Mapping file id7329 NCBI file	EvidenceIEA
GeneZCCHC8	AuthorityHGNC:25265	Mapping file id55596 NCBI file	EvidenceIEA
GeneZNF136	AuthorityHGNC:12920	Mapping file id7695 NCBI file	EvidenceIEA, TAS
GeneZNF141	AuthorityHGNC:12926	Mapping file id7700 NCBI file	EvidenceIEA, TAS
GeneZNF224	AuthorityHGNC:13017	Mapping file id7767 NCBI file	EvidenceIEA, TAS
GeneZNF257	AuthorityHGNC:13498	Mapping file id113835 NCBI file	EvidenceIEA, TAS
GeneZNF264	AuthorityHGNC:13057	Mapping file id9422 NCBI file	EvidenceIEA, TAS
GeneZNF273	AuthorityHGNC:13067	Mapping file id10793 NCBI file	EvidenceIEA, TAS
GeneZNF28	AuthorityHGNC:13073	Mapping file id7576 NCBI file	EvidenceIEA, TAS
GeneZNF30	AuthorityHGNC:13090	Mapping file id90075 NCBI file	EvidenceIEA, TAS
GeneZNF317	AuthorityHGNC:13507	Mapping file id57693 NCBI file	EvidenceIEA, TAS
GeneZNF320	AuthorityHGNC:13842	Mapping file id162967 NCBI file	EvidenceIEA, TAS
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
Geneno symbol in the identity file	Authoritynone	Mapping file idKJ852773 as written	EvidenceIEA, TAS
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

Epigenetic regulation of gene expressionR-HSA-212165325 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.