Pathway Human Homo sapiens

Transcriptional Regulation by MECP2

R-HSA-8986944 in Reactome release 97: under Generic Transcription Pathway, with 65 genes placed in it by the mapping files and 5 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-8986944 (mouse), R-RNO-8986944 (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-8986944.4
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2018-09-12
Events inside: 22, counted from the record

MECP2 is an X chromosome gene whose loss-of-function mutations are an underlying cause of the majority of Rett syndrome cases. The MECP2 gene locus consists of four exons. Both exon 1 and exon 2 contain translation start sites. Alternative splicing of the second exon results in expression of two MECP2 transcript isoforms, MECP2_e1 (MECP2B or MECP2alpha) and MECP2_e2 (MECP2A or MECP2beta). The N-terminus of the MECP2_e1 isoform, in which exon 2 is spliced out, is encoded by exon 1. The N-terminus of the MECP2_e2 isoforms, which includes both exon 1 and exon 2, is encoded by exon 2, as the exon 2 translation start site is used. Exons 3 and 4 are present in both isoforms. The MECP2_e2 isoform was cloned first and is therefore more extensively studied. The MECP2_e1 isoform is more abundant in the brain (Mnatzakanian et al. 2004, Kriaucionis and Bird 2004, Kaddoum et al. 2013). Mecp2 isoforms show different expression patterns during mouse brain development and in adult brain regions (Dragich et al. 2007, Olson et al. 2014). While Rett syndrome mutations mainly occur in exons 3 and 4 of MECP2, thereby affecting both MECP2 isoforms (Mnatzakanian et al. 2004), some mutations occur in exon 1, affecting MECP2_e1 only. No mutations have been described in exon 2 (Gianakopoulos et al. 2012). Knockout of Mecp2_e1 isoform in mice, through a naturally occurring Rett syndrome point mutation which affects the first translation codon of MECP2_e1, recapitulates Rett-like phenotype. Knockout of Mecp2_e2 isoform in mice does not result in impairment of neurologic functions (Yasui et al. 2014). In Mecp2 null mice, transgenic expression of either Mecp2_e1 or Mecp2_e2 prevents development of Rett-like phenotype, with Mecp2_e1 rescuing more Rett-like symptoms than Mecp2_e2. This indicates that both splice variants can fulfill basic Mecp2 functions in the mouse brain (Kerr et al. 2012). Changes in gene expression upon over-expression of either MECP2_e1 or MECP2_e2 imply overlapping as well as distinct target genes (Orlic-Milacic et al. 2014).

Methyl-CpG-binding protein 2 encoded by the MECP2 gene binds to methylated CpG sequences in the DNA. The binding is not generic, however, but is affected by the underlying DNA sequence (Yoon et al. 2003). MECP2 binds to DNA containing 5 methylcytosine (5mC DNA), a DNA modification associated with transcriptional repression (Mellen et al. 2012), both in the context of CpG islands and outside of CpG islands (Chen et al. 2015). In addition, MECP2 binds to DNA containing 5 hydroxymethylcytosine (5hmC DNA), a DNA modification associated with transcriptional activation (Mellen et al. 2012). MECP2 binds to DNA as a monomer, occupying about 11 bp of the DNA. Binding of one MECP2 molecule facilitates binding of the second MECP2 molecule, and therefore clustering can occur at target sites. MECP2 binding to chromatin may be facilitated by nucleosome methylation (Ghosh et al. 2010).

MECP2 was initially proposed to act as a generic repressor of gene transcription. However, high throughput studies of MECP2-induced changes in gene expression in mouse hippocampus (Chahrour et al. 2008), and mouse and human cell lines (Orlic-Milacic et al. 2014) indicate that more genes are up-regulated than down-regulated when MECP2 is overexpressed. At least for some genes directly upregulated by MECP2, it was shown that a complex of MECP2 and CREB1 was involved in transcriptional stimulation (Chahrour et al. 2008, Chen et al. 2013).

MECP2 expression is the highest in postmitotic neurons compared to other cell types, with MECP2 being almost as abundant as core histones. Phosphorylation of MECP2 in response to neuronal activity regulates binding of MECP2 to DNA, suggesting that MECP2 may remodel chromatin in a neuronal activity-dependent manner. The resulting changes in gene expression would then modulate synaptic plasticity and behavior (reviewed by Ebert and Greenberg 2013). In human embryonic stem cell derived Rett syndrome neurons, loss of MECP2 is associated with a significant reduction in transcription of neuronally active genes, as well as the reduction in nascent protein synthesis. The reduction in nascent protein synthesis can at least in part be attributed to the decreased activity of the PI3K/AKT/mTOR signaling pathway. Neuronal morphology (reduced soma size) and the level of protein synthesis in Rett neurons can be ameliorated by treating the cells with growth factors which activate the PI3K/AKT/mTOR cascade or by inhibition of PTEN, the negative regulator of AKT activation. Mitochondrial gene expression is also downregulated in Rett neurons, which is associated with a reduced capacity of the mitochondrial electron transport chain (Ricciardi et al. 2011, Li et al. 2013). Treatment of Mecp2 null mice with IGF1 (insulin-like growth factor 1) reverses or ameliorates some Rett-like features such as locomotion, respiratory difficulties and irregular heart rate (Tropea et al. 2009).

MECP2 regulates expression of a number of ligands and receptors involved in neuronal development and function. Ligands regulated by MECP2 include BDNF (reviewed by Li and Pozzo-Miller 2014, and KhorshidAhmad et al. 2016), CRH (McGill et al. 2006, Samaco et al. 2012), SST (Somatostatin) (Chahrour et al. 2008), and DLL1 (Li et al. 2014). MECP2 also regulates transcription of genes involved in the synthesis of the neurotransmitter GABA – GAD1 (Chao et al. 2010) and GAD2 (Chao et al. 2010, He et al. 2014). MECP2 may be involved in direct stimulation of transcription from the GLUD1 gene promoter, encoding mitochondrial glutamate dehydrogenase 1, which may be involved in the turnover of the neurotransmitter glutamate (Livide et al. 2015). Receptors regulated by MECP2 include glutamate receptor GRIA2 (Qiu et al. 2012), NMDA receptor subunits GRIN2A (Durand et al. 2012) and GRIN2B (Lee et al. 2008), opioid receptors OPRK1 (Chahrour et al. 2008) and OPRM1 (Hwang et al. 2009, Hwang et al. 2010, Samaco et al. 2012), GPRIN1 (Chahrour et al. 2008), MET (Plummer et al. 2013), NOTCH1 (Li et al. 2014). Channels/transporters regulated by MECP2 include TRPC3 (Li et al. 2012) and SLC2A3 (Chen et al. 2013). MECP2 regulates transcription of FKBP5, involved in trafficking of glucocorticoid receptors (Nuber et al. 2005, Urdinguio et al. 2008). MECP2 is implicated in regulation of expression of SEMA3F (semaphorin 3F) in mouse olfactory neurons (Degano et al. 2009). In zebrafish, Mecp2 is implicated in sensory axon guidance by direct stimulation of transcription of Sema5b and Robo2 (Leong et al. 2015). MECP2 may indirectly regulate signaling by neuronal receptor tyrosine kinases by regulating transcription of protein tyrosine phosphatases, PTPN1 (Krishnan et al. 2015) and PTPN4 (Williamson et al. 2015).

MECP2 regulates transcription of several transcription factors involved in functioning of the nervous system, such as CREB1, MEF2C, RBFOX1 (Chahrour et al. 2008) and PPARG (Mann et al. 2010, Joss-Moore et al. 2011).

MECP2 associates with transcription and chromatin remodeling factors, such as CREB1 (Chahrour et al. 2008, Chen et al. 2013), the HDAC1/2-containing SIN3A co-repressor complex (Nan et al. 1998), and the NCoR/SMRT complex (Lyst et al. 2013, Ebert et al. 2013). There are contradictory reports on the interaction of MECP2 with the SWI/SNF chromatin-remodeling complex (Harikrishnan et al. 2005, Hu et al. 2006). Interaction of MECP2 with the DNA methyltransferase DNMT1 has been reported, with a concomitant increase in enzymatic activity of DNMT1 (Kimura and Shiota 2003).

In addition to DNA binding-dependent regulation of gene expression by MECP2, MECP2 may influence gene expression by interaction with components of the DROSHA microprocessor complex and the consequent change in the levels of mature microRNAs (Cheng et al. 2014, Tsujimura et al. 2015).

Increased MECP2 promoter methylation is observed in both male and female autism patients (Nagarajan et al. 2008). Regulatory elements that undergo methylation are found in the promoter and the first intron of MECP2 and their methylation was shown to regulate Mecp2 expression in mice (Liyanage et al. 2013). Mouse Mecp2 promoter methylation was shown to be affected by stress (Franklin et al. 2010).

The Rett-like phenotype of Mecp2 null mice is reversible (Guy et al. 2007), but appropriate levels of Mecp2 expression need to be achieved (Alvarez-Saavedra et al. 2007). When Mecp2 expression is restored in astrocytes of Mecp2 null mice, amelioration of Rett symptoms occurs, involving non-cell-autonomous positive effect on mutant neurons and increasing level of the excitatory glutamate transporter VGLUT1 (Lioy et al. 2011). Microglia derived from Mecp2 null mice releases higher than normal levels of glutamate, which has toxic effect on neurons. Increased glutamate secretion may be due to increased levels of glutaminase (Gls), involved in glutamate synthesis, and increased levels of connexin-32 (Gjb1), involved in glutamate release, in Mecp2 null microglia (Maezawa and Jin 2010). Targeted deletion of Mecp2 from Sim1-expressing neurons of the mouse hypothalamus recapitulates some Rett syndrome-like features and highlights the role of Mecp2 in feeding behavior and response to stress (Fyffe et al. 2008).

Mecp2 overexpression, similar to MECP2 duplication syndrome, causes neurologic phenotype similar to Rett (Collins et al. 2004, Luikenhuis et al. 2004, Van Esch et al. 2005, Alvarez-Saavedra 2007, Van Esch et al. 2012). The phenotype of the mouse model of the MECP2 duplication syndrome in adult mice is reversible when Mecp2 expression levels are corrected (Sztainberg et al. 2015).

Literature Reactome attaches

Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological functionProc. Natl. Acad. Sci. U.S.A., 2009, vol. 106, p. 4882-7PubMed 19225110
MeCP2 deficiency disrupts axonal guidance, fasciculation, and targeting by altering Semaphorin 3F functionMol. Cell. Neurosci., 2009, vol. 42, p. 243-54PubMed 19628041
GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cellsEur. J. Hum. Genet., 2015, vol. 23, p. 195-201PubMed 24916645
A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndromeNat. Genet., 2004, vol. 36, p. 339-41PubMed 15034579
Developmental Dynamics of Rett SyndromeNeural Plast., 2016, vol. 2016, p. 6154080PubMed 26942018
Over-expression of either MECP2_e1 or MECP2_e2 in neuronally differentiated cells results in different patterns of gene expressionPLoS ONE, 2014, vol. 9, p. e91742PubMed 24699272
N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso

Reactome's record lists 7 orthologous events, R-RNO-8986944 (Rattus norvegicus), R-MMU-8986944 (Mus musculus) among the species this site serves, and 5 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-10-01 ET · Reactome pathway browser"Transcriptional Regulation by MECP2". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-8986944 with StableID: R-HSA-8986944.4 (accessed 2026-10-01 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 65 genes in this human pathway; showing 1 to 65, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneAGO1	AuthorityHGNC:3262	Mapping file id26523 NCBI file	EvidenceIEA, TAS
GeneAGO2	AuthorityHGNC:3263	Mapping file id27161 NCBI file	EvidenceIEA, TAS
GeneAGO3	AuthorityHGNC:18421	Mapping file id192669 NCBI file	EvidenceIEA, TAS
GeneAGO4	AuthorityHGNC:18424	Mapping file id192670 NCBI file	EvidenceIEA, TAS
GeneAURKB	AuthorityHGNC:11390	Mapping file id9212 NCBI file	EvidenceIEA
GeneBDNF	AuthorityHGNC:1033	Mapping file id627 NCBI file	EvidenceIEA
GeneCALM1	AuthorityHGNC:1442	Mapping file id801 NCBI file	EvidenceIEA
GeneCALM2	AuthorityHGNC:1445	Mapping file id805 NCBI file	EvidenceIEA
GeneCALM3	AuthorityHGNC:1449	Mapping file id808 NCBI file	EvidenceIEA
GeneCAMK2A	AuthorityHGNC:1460	Mapping file id815 NCBI file	EvidenceIEA
GeneCAMK2B	AuthorityHGNC:1461	Mapping file id816 NCBI file	EvidenceIEA
GeneCAMK2D	AuthorityHGNC:1462	Mapping file id817 NCBI file	EvidenceIEA
GeneCAMK2G	AuthorityHGNC:1463	Mapping file id818 NCBI file	EvidenceIEA
GeneCAMK4	AuthorityHGNC:1464	Mapping file id814 NCBI file	EvidenceIEA
GeneCREB1	AuthorityHGNC:2345	Mapping file id1385 NCBI file	EvidenceIEA
GeneCRH	AuthorityHGNC:2355	Mapping file id1392 NCBI file	EvidenceIEA
GeneDGCR8	AuthorityHGNC:2847	Mapping file id54487 NCBI file	EvidenceIEA
GeneDLL1	AuthorityHGNC:2908	Mapping file id28514 NCBI file	EvidenceIEA
GeneFKBP5	AuthorityHGNC:3721	Mapping file id2289 NCBI file	EvidenceIEA
GeneFOXG1	AuthorityHGNC:3811	Mapping file id2290 NCBI file	EvidenceIEA
GeneGAD1	AuthorityHGNC:4092	Mapping file id2571 NCBI file	EvidenceIEA
GeneGAD2	AuthorityHGNC:4093	Mapping file id2572 NCBI file	EvidenceIEA
GeneGAMT	AuthorityHGNC:4136	Mapping file id2593 NCBI file	EvidenceIEA
GeneGPRIN1	AuthorityHGNC:24835	Mapping file id114787 NCBI file	EvidenceIEA
GeneGPS2	AuthorityHGNC:4550	Mapping file id2874 NCBI file	EvidenceIEA
GeneGRIA2	AuthorityHGNC:4572	Mapping file id2891 NCBI file	EvidenceIEA
GeneGRIN2A	AuthorityHGNC:4585	Mapping file id2903 NCBI file	EvidenceIEA
GeneGRIN2B	AuthorityHGNC:4586	Mapping file id2904 NCBI file	EvidenceIEA
GeneHDAC1	AuthorityHGNC:4852	Mapping file id3065 NCBI file	EvidenceIEA, TAS
GeneHDAC2	AuthorityHGNC:4853	Mapping file id3066 NCBI file	EvidenceIEA, TAS
GeneHDAC3	AuthorityHGNC:4854	Mapping file id8841 NCBI file	EvidenceIEA
GeneHIPK2	AuthorityHGNC:14402	Mapping file id28996 NCBI file	EvidenceTAS
GeneHTT	AuthorityHGNC:4851	Mapping file id3064 NCBI file	EvidenceIEA
GeneIRAK1	AuthorityHGNC:6112	Mapping file id3654 NCBI file	EvidenceIEA
GeneLBR	AuthorityHGNC:6518	Mapping file id3930 NCBI file	EvidenceTAS
GeneMECP2	AuthorityHGNC:6990	Mapping file id4204 NCBI file	EvidenceIEA, TAS
GeneMEF2C	AuthorityHGNC:6996	Mapping file id4208 NCBI file	EvidenceIEA
GeneMET	AuthorityHGNC:7029	Mapping file id4233 NCBI file	EvidenceTAS
GeneMIR132	AuthorityHGNC:31516	Mapping file idENSG00000267200 Ensembl file	EvidenceIEA
GeneMIR137	AuthorityHGNC:31523	Mapping file idENSG00000284202 Ensembl file	EvidenceIEA
GeneMOBP	AuthorityHGNC:7189	Mapping file id4336 NCBI file	EvidenceIEA
GeneMOV10	AuthorityHGNC:7200	Mapping file id4343 NCBI file	EvidenceIEA, TAS
GeneNCOR1	AuthorityHGNC:7672	Mapping file id9611 NCBI file	EvidenceIEA
GeneNCOR2	AuthorityHGNC:7673	Mapping file id9612 NCBI file	EvidenceIEA
GeneNOTCH1	AuthorityHGNC:7881	Mapping file idENSG00000148400 Ensembl file	EvidenceIEA
GeneOPRK1	AuthorityHGNC:8154	Mapping file id4986 NCBI file	EvidenceIEA
GeneOPRM1	AuthorityHGNC:8156	Mapping file id4988 NCBI file	EvidenceIEA
GenePPARG	AuthorityHGNC:9236	Mapping file id5468 NCBI file	EvidenceIEA
GenePRKACA	AuthorityHGNC:9380	Mapping file id5566 NCBI file	EvidenceIEA
GenePTEN	AuthorityHGNC:9588	Mapping file id5728 NCBI file	EvidenceTAS
GenePTPN1	AuthorityHGNC:9642	Mapping file id5770 NCBI file	EvidenceTAS
GenePTPN4	AuthorityHGNC:9656	Mapping file id5775 NCBI file	EvidenceTAS
GenePVALB	AuthorityHGNC:9704	Mapping file id5816 NCBI file	EvidenceIEA
GeneRBFOX1	AuthorityHGNC:18222	Mapping file id54715 NCBI file	EvidenceIEA
GeneSGK1	AuthorityHGNC:10810	Mapping file id6446 NCBI file	EvidenceIEA
GeneSIN3A	AuthorityHGNC:19353	Mapping file id25942 NCBI file	EvidenceIEA, TAS
GeneSLC2A3	AuthorityHGNC:11007	Mapping file id6515 NCBI file	EvidenceIEA
GeneSOX2	AuthorityHGNC:11195	Mapping file id6657 NCBI file	EvidenceIEA
GeneSST	AuthorityHGNC:11329	Mapping file id6750 NCBI file	EvidenceIEA
GeneTBL1X	AuthorityHGNC:11585	Mapping file id6907 NCBI file	EvidenceIEA
GeneTBL1XR1	AuthorityHGNC:29529	Mapping file id79718 NCBI file	EvidenceIEA
GeneTNRC6A	AuthorityHGNC:11969	Mapping file id27327 NCBI file	EvidenceIEA, TAS
GeneTNRC6B	AuthorityHGNC:29190	Mapping file id23112 NCBI file	EvidenceIEA, TAS
GeneTNRC6C	AuthorityHGNC:29318	Mapping file id57690 NCBI file	EvidenceIEA, TAS
GeneTRPC3	AuthorityHGNC:12335	Mapping file id7222 NCBI file	EvidenceIEA

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

Generic Transcription PathwayR-HSA-2124361,251 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.