Brn1/2/4 (Sp-Brn1/2/4, brn1/2/4) — curation notes

UniProt A0A7M7GMA5 (unreviewed, "POU domain protein", 467 aa), GeneID 577601 (NCBI gene
description "brain 1/2/4", alias brn1/2/4, other designation "POU domain, class 3,
transcription factor 4"), PANTHER PTHR11636:SF89. Organism Strongylocentrotus purpuratus
(NCBITaxon:7668).

Identity of the UniProt entry

• The UniProt entry carries no literature RX lines; it is a genome-project translation
  (RefSeq XP_003729178.1 / LOC577601). Identity with the GRN gene rests on (i) the NCBI
  Gene record for 577601, whose description is "brain 1/2/4" with alias "brn1/2/4" and
  designation "POU domain, class 3, transcription factor 4", retrieved via eutils; (ii) the
  PANTHER subfamily PTHR11636:SF89 (a class III POU / Brn-related subfamily) and PROSITE
  POU-specific + homeobox domains, matching the Yuh et al. description of a POU factor
  "related closely to the mammalian factors Brain-1, -2, and -4"; and (iii) the single
  class III POU gene in the sea urchin genome, for which the human Brn1/Brn2/Brn4/Oct6 are
  equal co-orthologs PMID:30450080.
• Confidence that A0A7M7GMA5 is the brn1/2/4 of the Davidson endoderm GRN: HIGH.

What the gene is

• Cloned as the predicted midgut regulator of endo16 PMID:15893979.
• Class III POU homeodomain TF (POU-specific domain 219-293, homeodomain 309-369 in the
  UniProt entry); in vertebrates the class III POU genes are neural regulators
  PMID:26657764.

Expression

• Maternal transcripts decay to undetectable at blastula PMID:26657764.
• Zygotic activation in the endoderm: first detectable in the 20-h blastula at ~100
  molecules/embryo, then an abrupt 10-fold rise at the onset of gastrulation; late endo16
  rise follows that of brn1/2/4 PMID:15893979.
• Spatial domain in the gut: Yuh et al. described it as confined to the midgut
  PMID:15893979, whereas a
  later FISH study assigns the endodermal domain to the foregut and adds two ectodermal
  domains PMID:19250980. The discrepancy
  (midgut vs foregut) is unresolved in the cached literature; it may reflect stage or
  probe/method differences. Both studies agree that the gene is a gut-endoderm regulatory
  gene.
• In the Peter & Davidson 2011 endoderm GRN, brn1/2/4 is one of the regulatory genes that
  come on in veg2-derived (anterior endoderm) cells in the last hours before gastrulation
  PMID:21623371.

Place in the endoderm GRN

• Input: Blimp1 (veg2 endoderm) activates brn1/2/4 PMID:21623371. The veg1 regulator Eve affects it only
  indirectly, through a proposed veg1-to-veg2 signal PMID:21623371.
• Upstream of it sit the post-gastrular midgut specification genes PMID:15893979.
• Output 1, endo16 (the midgut differentiation gene whose cis-regulatory analysis predicted
  this factor): Brn1/2/4 MASO blocks the late phase of endo16 transcription and abolishes
  expression driven by cis-regulatory Module B, leaving Module A untouched PMID:15893979. This is a module-specific, sign-
  positive effect, i.e. Brn1/2/4 is an activator acting through Module B.
• Output 2 (predicted site): the blimp1/krox 1a midgut/hindgut cis-regulatory module
  carries Brn1/2/4 sites PMID:16798107.
• The brief for this review mentioned brn1/2/4 inputs into foxa and gatae; the cached
  Peter & Davidson 2011 text does not state these linkages explicitly (they would be in
  Fig. 4 / the supplementary perturbation tables), so they are not asserted here.
• Not present in Smith & Davidson 2008 (PMID:19104065) or Peter & Davidson 2010
  (PMID:19895806, pre-mid-blastula GRN): consistent with its late (>20 h) activation.

Second role: neurogenesis

• Wei, Angerer & Angerer 2016 placed Brn1/2/4 downstream of SoxC in the neurogenic pathway
  PMID:26657764 and PMID:26657764.
• SoxC MASO removes the scattered ectodermal (neural precursor) Brn1/2/4 expression but
  not the foregut expression PMID:26657764, so the endodermal and neural inputs are
  separate.
• Later larval neurons co-expressing SpLox and Brn1/2/4 are lateral ganglion neurons with a
  "pre-pancreatic" signature PMID:30450080.

GOA audit summary

• All 10 GOA rows are electronic (4 IBA from PAINT node PTN000180816, 6 IEA). The TF rows
  (GO:0000981, GO:0000978, GO:0006357, nucleus) are directly supported on the target by the
  endo16 Module B MASO result; the generic parents (GO:0003677, GO:0003700, GO:0006351,
  GO:0006355) are proposed for MODIFY to their Pol II-specific children. GO:0090575
  (transcription regulator complex) has no sea urchin evidence and is kept as non-core.
• NEW: GO:0001228 (activator activity, IMP), GO:0045944 (IMP), GO:0048565 digestive tract
  development (IMP, via endo16 gut differentiation gene), GO:0045666 positive regulation of
  neuron differentiation (IMP, Wei 2016).