Pathway Human Homo sapiens

Expression of BMAL (ARNTL), CLOCK, and NPAS2

R-HSA-9931509 in Reactome release 97: under Circadian clock, with 35 genes placed in it by the mapping files and 0 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; neither of the other two lists holds it. 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-9931509.1
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2025-03-26
Events inside: 10, counted from the record

BMAL1 (ARNTL), CLOCK, and NPAS2, which acts redundantly with CLOCK, are key activators of diurnal circadian gene expression (reviewed in Cox and Takahashi 2019). Their expression is positively regulated by the Retinoid-related orphan receptors RORA, RORB, and RORC and negatively regulated by the nuclear receptor NR1D1 (REV-ERBA), all of which complete for the same ROR responsive elements (RRE, RORE) (inferred from mouse homologs in Ueda et al. 2002, Guilaumond et al. 2005) in the BMAL1 promoter (inferred from the mouse homolog in Sato et al. 2004, Akashi and Takumi 2005, Guillaumond et al. 2005, Takeda et al. 2012) and CLOCK promoter (inferred from mouse homologs in Lau et al. 2004, Takeda et al. 2012). ROR nuclear receptors bind oxysterols (Wang et al. 2010) while NR1D1 binds heme (Yin et al. 2007, Raghuram et al. 2007), thus providing potential links with metabolism.

ROR nuclear receptors recruit coactivators of transcription such as EP300 (p300), PPARGC1A (PGC1A) (inferred from mouse homologs in Lau et al. 2004), and NRIP1 (Poliandri et al. 2011) to activate transcription by RNA polymerase II. In contrast, heme-bound NR1D1 recruits the corepressor NCOR1, and the histone deacetylase HDAC3 to repress transcription (Wu et al. 2009).

The genes encoding RORA, RORC, and NR1D1 regulate BMAL1 and CLOCK and are regulated by BMAL1 and CLOCK, thereby constituting a secondary loop in the mammalian circadian clock.

Literature Reactome attaches

Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptorsJ Biol Rhythms, 2005, vol. 20, p. 391-403PubMed 16267379
The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1Nat Struct Mol Biol, 2005, vol. 12, p. 441-8PubMed 15821743
A functional genomics strategy reveals Rora as a component of the mammalian circadian clockNeuron, 2004, vol. 43, p. 527-37PubMed 15312651
A transcription factor response element for gene expression during circadian nightNature, 2002, vol. 418, p. 534-9PubMed 12152080
RORγ directly regulates the circadian expression of clock genes and downstream targets in vivoNucleic Acids Res, 2012, vol. 40, p. 8519-35PubMed 22753030
RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of RORJ Biol Chem, 2004, vol. 279, p. 36828-40PubMed 15199055
Modulation of clock gene expression by the transcriptional coregulator receptor interacting protein 140 (RIP140)J. Biol. Rhythms, 2011, vol. 26, p. 187-99PubMed 21628546
Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalphaGenes Dev, 2009, vol. 23, p. 2201-9PubMed 19710360
Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathwaysScience, 2007, vol. 318, p. 1786-9PubMed 18006707
Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbetaNat Struct Mol Biol, 2007, vol. 14, p. 1207-13PubMed 18037887
Modulation of retinoic acid receptor-related orphan receptor alpha and gamma activity by 7-oxygenated sterol ligandsJ Biol Chem, 2010, vol. 285, p. 5013-25PubMed 19965867
Circadian clock genes and the transcriptional architecture of the clock mechanismJ Mol Endocrinol, 2019, vol. 63, p. R93-R102PubMed 31557726

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Expression of BMAL (ARNTL), CLOCK, and NPAS2". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9931509 with StableID: R-HSA-9931509.1 (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 35 genes in this human pathway; showing 1 to 35, 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
GeneATF2	AuthorityHGNC:784	Mapping file id1386 NCBI file	EvidenceIEA
GeneBMAL1	AuthorityHGNC:701	Mapping file id406 NCBI file	EvidenceIEA
GeneCARM1	AuthorityHGNC:23393	Mapping file id10498 NCBI file	EvidenceIEA
GeneCHD9	AuthorityHGNC:25701	Mapping file id80205 NCBI file	EvidenceIEA
GeneCLOCK	AuthorityHGNC:2082	Mapping file id9575 NCBI file	EvidenceIEA
GeneCREB1	AuthorityHGNC:2345	Mapping file id1385 NCBI file	EvidenceIEA
GeneCREBBP	AuthorityHGNC:2348	Mapping file id1387 NCBI file	EvidenceIEA
GeneCRTC1	AuthorityHGNC:16062	Mapping file id23373 NCBI file	EvidenceIEA
GeneCRTC2	AuthorityHGNC:27301	Mapping file id200186 NCBI file	EvidenceIEA
GeneCRTC3	AuthorityHGNC:26148	Mapping file id64784 NCBI file	EvidenceIEA
GeneEP300	AuthorityHGNC:3373	Mapping file id2033 NCBI file	EvidenceIEA
GeneHDAC3	AuthorityHGNC:4854	Mapping file id8841 NCBI file	EvidenceIEA, TAS
GeneHELZ2	AuthorityHGNC:30021	Mapping file id85441 NCBI file	EvidenceIEA
GeneMED1	AuthorityHGNC:9234	Mapping file id5469 NCBI file	EvidenceIEA
GeneMEF2C	AuthorityHGNC:6996	Mapping file id4208 NCBI file	EvidenceIEA
GeneMEF2D	AuthorityHGNC:6997	Mapping file id4209 NCBI file	EvidenceIEA
GeneNCOA1	AuthorityHGNC:7668	Mapping file id8648 NCBI file	EvidenceIEA
GeneNCOA2	AuthorityHGNC:7669	Mapping file id10499 NCBI file	EvidenceIEA
GeneNCOA6	AuthorityHGNC:15936	Mapping file id23054 NCBI file	EvidenceIEA
GeneNCOR1	AuthorityHGNC:7672	Mapping file id9611 NCBI file	EvidenceIEA, TAS
GeneNPAS2	AuthorityHGNC:7895	Mapping file id4862 NCBI file	EvidenceIEA
GeneNR1D1	AuthorityHGNC:7962	Mapping file id9572 NCBI file	EvidenceIEA, TAS
GeneNRIP1	AuthorityHGNC:8001	Mapping file id8204 NCBI file	EvidenceIEA
GenePPARA	AuthorityHGNC:9232	Mapping file id5465 NCBI file	EvidenceIEA
GenePPARGC1A	AuthorityHGNC:9237	Mapping file id10891 NCBI file	EvidenceIEA
GeneRAI1	AuthorityHGNC:9834	Mapping file id10743 NCBI file	EvidenceIEA
GeneRORA	AuthorityHGNC:10258	Mapping file id6095 NCBI file	EvidenceIEA
GeneRORB	AuthorityHGNC:10259	Mapping file id6096 NCBI file	EvidenceIEA
GeneRORC	AuthorityHGNC:10260	Mapping file id6097 NCBI file	EvidenceIEA
GeneRXRA	AuthorityHGNC:10477	Mapping file id6256 NCBI file	EvidenceIEA
GeneSIRT1	AuthorityHGNC:14929	Mapping file id23411 NCBI file	EvidenceIEA
GeneSMARCD3	AuthorityHGNC:11108	Mapping file id6604 NCBI file	EvidenceIEA
GeneTBL1X	AuthorityHGNC:11585	Mapping file id6907 NCBI file	EvidenceIEA
GeneTBL1XR1	AuthorityHGNC:29529	Mapping file id79718 NCBI file	EvidenceIEA
GeneTGS1	AuthorityHGNC:17843	Mapping file id96764 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

Circadian clockR-HSA-9909396112 genes

Children

None: no pathway of this release's list names this one as a parent.

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.