BHLHE40 (DEC1 / STRA13 / SHARP2) review notes

No deep-research provider keys were available; this file records a manual literature
survey (Europe PMC searches, papers cached with ai-gene-review fetch-pmid).
UniProt: O14503 (human), mouse ortholog O35185.

Identity and domain architecture

• 412 aa class E bHLH-Orange protein; bHLH domain 52-107 and Orange domain 142-175
  (UniProt FT, PROSITE-ProRule), PANTHER PTHR10985 (HES-related), InterPro HES_HEY.
• Cloned from Bt2cAMP-differentiated human chondrocytes PMID:9240428; mouse Stra13 cloned as
  a retinoic acid-inducible gene PMID:9284045.
• Unlike HES proteins it lacks the C-terminal WRPW Groucho-binding motif
  PMID:10737769.

Molecular function: E-box DNA-binding repressor

• Binds class B CACGTG E-boxes as a homodimer PMID:12297495.
• Represses DEC2 promoter via proximal E-box; DNA-binding mutants inactive
  PMID:12624110.
• Represses mPer1 via DNA binding, not BMAL1 interaction PMID:15193144.
• Arg65 needed for E-box binding, BMAL1 interaction and repression; DEC1-DEC2
  heterodimer by pull-down PMID:15560782.
• ChIP/EMSA/reporter: binds E but not E' boxes PMID:18411297.
• Repression mechanisms: HDAC1-dependent (autorepression) and HDAC-independent via TFIIB
  interaction (c-Myc repression) PMID:10737769.
• Corepressor of RXR and RXR heterodimers through an LXXLL motif [PMID:19786558 "DEC1 and
  DEC2 interacted directly with RXRalpha, and ligand addition enhanced their association";
  "an LXXLL motif in DEC1 and DEC2 is necessary for RXRalpha repression"]; IL-6 enhances
  DEC1-RXRalpha association PMID:29234281.
• Context-dependent effects through p53: mouse Stra13 binds p53 and stabilizes it
  PMID:17347673; human DEC1 binds p53 on the MIC-1 promoter and attenuates p53
  transactivation of MIC-1 PMID:22723347.

Circadian clock

• Fifth clock-gene family; represses CLOCK/BMAL1-activated Per1; light-inducible in SCN
  PMID:12397359.
• DEC autofeedback loop: CLOCK/BMAL activates Dec1 through three CACGTG E-boxes, and DEC1/2,
  PER and CRY repress it PMID:14672706.
• Dec1-/- mice: slightly longer free-running period and faster re-entrainment
  PMID:18411297.
• Clock-output targets: SHP/NR0B2 PMID:28797635, ATP1B1 and blood pressure
  PMID:30012868.

Hypoxia

• HIF-1 target: functional HREs in the DEC1 promoter PMID:12354771; VHL/hypoxia-regulated and overexpressed in clear-cell renal
  carcinoma PMID:11278694.
• Effector of hypoxic inhibition of adipogenesis by repressing PPARG2 (mouse)
  PMID:11879638.
• Hypoxia induction is an expression response; I did not add a hypoxia process term.

Immune functions (mostly mouse)

• Stra13-/- mice: defective CD4 T cell activation, late-onset autoimmunity
  PMID:11668339.
• T cells: Bhlhe40 promotes GM-CSF and represses IL-10; required for EAE
  PMID:24699451; ChIP-seq peaks at Il3/Csf2 and Il10 loci.
• Mtb infection: essential repressor of Il10; binds +6 kb Il10 element PMID:29773644.
• Macrophages: required cell-intrinsically for large peritoneal macrophage self-renewal;
  represses Maf/Mafb (ChIP peak at Maf promoter) PMID:31061528; with Bhlhe41 regulates
  alveolar macrophage self-renewal and identity PMID:31414712.
• Efferocytosis-induced macrophage proliferation: Myc induces Bhlhe40, which represses
  c-Maf PMID:34784501. This is one context of the wider LPM proliferation programme and is not
  treated as the gene's defining function.
• Tissue-resident memory CD8 T cells and TILs: Bhlhe40 sustains mitochondrial fitness
  PMID:31533057.

Localization and PTMs

• Mostly nuclear, with some cytoplasmic protein; SUMOylation at K159/K279 stabilizes it
  and enhances repression PMID:21829689; ubiquitin/proteasome turnover
  PMID:11278694.

Curation decisions summary

• Core: RNA Pol II-specific DNA-binding transcription repressor activity at CACGTG E-boxes
  (GO:0001227, GO:0070888), negative regulation of Pol II transcription (GO:0000122) and
  circadian regulation of gene expression (GO:0032922); nucleus.
• 82 bare protein-binding rows: MODIFY to informative terms where a small-scale study
  supports one (RXRA → nuclear retinoid X receptor binding; p53 → p53 binding; BMAL1 → bHLH
  transcription factor binding), REMOVE for high-throughput Y2H, viral and UBC9 rows.
• IBA anterior/posterior pattern specification: HES-subfamily (segmentation clock)
  function, with no DEC-specific evidence and normal development in knockout mice →
  MARK_AS_OVER_ANNOTATED.
• NEW (conservative): transcription corepressor activity (RXR, IDA PMID:19786558);
  negative regulation of interleukin-10 production and positive regulation of
  macrophage proliferation (ISS from mouse; direct binding at Il10 and Maf loci shown by
  ChIP-seq).