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ASCL1

achaete-scute family bHLH transcription factor 1
2 disorders 2 no genetic record 12q23.2 gene with protein product
HGNC:738MonarchNCBI Gene 429ENSG00000139352UniProt P50553OMIM 100790

Aliases: ASH1, HASH1, bHLHa46.

Normal function · from ai-gene-review (P50553, commit 79fe13b38970) · AI-generated, not KB evidence

ASCL1 (Achaete-scute homolog 1, also known as MASH1/hASH1) is a proneural basic helix-loop-helix (bHLH) transcription factor that functions as both a classical transcriptional activator and a pioneer factor capable of accessing closed chromatin. It binds E-box motifs (CANNTG, particularly CACCTG) as a heterodimer with E-proteins (TCF3/E12/E47, TCF4) to activate neuronal and neuroendocrine gene programs. ASCL1 plays essential roles in neuronal differentiation, neuronal fate commitment, and neuroendocrine cell development. It is a master regulator of the SCLC-A (neuroendocrine) subtype of small cell lung cancer and directly activates targets including INSM1, MYT1, DLL1, and DLL3 (Notch pathway modulators). ASCL1 protein stability is regulated by CDK2-CyclinA2 phosphorylation, HUWE1-mediated ubiquitination, and protection via E-protein heterodimerization.

ASCL1 is a bHLH transcription factor that binds E-box motifs (CANNTG) as a heterodimer with E-proteins (TCF3, TCF4) and regulates transcription of neuronal target genes.
molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific
ASCL1 specifically binds E-box sequences with strong preference for the CAGCTG variant, which is enriched directly beneath 74% of ASCL1 binding peaks (PMID:21536733). This "GC" core E-box preference distinguishes ASCL1 from Neurog2 (which prefers CAGATG), explaining their distinct neuronal subtype outputs. E-proteins enhance ASCL1 binding to CAGSTG sequences through heterodimerization.
molecular function: E-box binding
ASCL1 functions as a pioneer factor capable of binding nucleosomal DNA and initiating chromatin remodeling at neuronal enhancers. Studies reveal ASCL1 operates through two distinct mechanisms: at ~23.5% of sites it functions as a classical pioneer factor binding closed chromatin independently, while at ~68% of sites it requires cooperation with mSWI/SNF chromatin remodeling complexes (PMID:36931659). ASCL1 binds chromatin marked by a trivalent signature (H3K9me3, H3K27ac, H3K4me1) and predominantly at distal enhancers (~63%) rather than promoters (~7%) (PMID:25753420).
molecular function: chromatin binding
ASCL1 heterodimerizes with E-proteins (TCF3/E12/E47, TCF4/E2-2) via its HLH domain. This dimerization is essential for DNA binding, transcriptional activity, and protein stability.
molecular function: bHLH transcription factor binding
ASCL1 forms heterodimers with E-proteins via its HLH domain, which is required for DNA binding and transcriptional function.
molecular function: protein dimerization activity
In the knowledge base · computed from kb/ at build time

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

DisorderRelationshipWhere the gene appears
Large Cell Neuroendocrine Carcinoma no genetic record
mechanism: Neuroendocrine Lineage Programme Expression
Neuroblastoma no genetic record
animal model: Xenopus anteroventral noradrenergic (AVNA) cell differentiation model

Identity from HGNC (snapshot 2026-10-01). Page layers are described in the gene pages documentation.