Erg (Strongylocentrotus purpuratus, UniProt Q6R7X7) - curation notes

Identity

• UniProt Q6R7X7 (Q6R7X7_STRPU, unreviewed/TrEMBL, 498 aa) is "Transcription
  factor Erg" deposited by Rizzo & Arnone (EMBL AY508725 / AAR92036.1, Dec 2003,
  submission title "Role of the sea urchin Erg homolog in mesenchyme formation").
  The RX line is PMID:11493577 (Zhu et al. 2001, the PMC EST project), which
  produced the EST from which the cDNA was recovered; that paper does not
  discuss erg as such. RefSeq NP_999833 / GeneID 397069; the CTD cross-reference
  is to human ERG (2078). Community symbol: Erg (Sp-Erg, erg in GRN papers).
• Domain architecture (UniProt FT): PNT/SAM-pointed domain 91-176 (PROSITE
  PS51433), ETS winged-helix DNA-binding domain 328-408 (PS50061), disordered
  N-terminal and central regions. CDD cd08531 "SAM_PNT-ERG_FLI-1", i.e. the
  ERG/FLI1 subfamily of ETS factors. PANTHER PTHR11849 (family label not written
  from memory). An earlier Lytechinus variegatus genomic fragment of the erg
  homolog defined the ERG/FLI-1-specific "R" region PMID:1457815.
• Identity check: the accession, the GRN gene "erg" (Oliveri 2008 ref 9 = Rizzo
  et al. 2006) and the Rizzo/Arnone "Sp-Erg" are the same gene; there is a
  single ERG-subfamily ets gene in the S. purpuratus genome
  PMID:16997294. No identity doubt.

Expression

• Genome-wide ets survey: PMID:16997294 Sp-Erg is not in the maternal set ("Five ets genes (Sp-Ets1/2,
  Sp-Tel, Sp-Pea, Sp-Ets4, Sp-Erf) are also maternally expressed"), i.e. it is
  zygotically activated in the skeletogenic micromere lineage.
• Later, oral non-skeletogenic mesoderm (NSM): PMID:23261933. Oral NSM erg
  is confined by the aboral regulators: PMID:23261933.

Place in the skeletogenic micromere GRN (Oliveri, Tu, Davidson 2008)

• Position: immediately downstream of the four double-negative-gate targets
  (alx1, ets1, tbr, tel), in the state-stabilization subcircuit:
  PMID:18413610
• Inputs: hex feeds back on erg ("the outputs of hex go to erg"); erg is
  downstream of ets1/alx1 per the GRN diagram (Fig. 3A). Perturbation basis:
  PMID:18413610.
• Outputs to differentiation genes (feed-forward architecture):
  [PMID:18413610 "these differentiation genes require as drivers products of all
  of the now familiar components of the skeletogenic regulatory state ( alx1 ,
  ets1 , tbr , tel , erg , hex , foxb , dri )" ... "Almost all of the linkages to
  the differentiation genes are feeds forward (A > C; A > B; B > C)" ... "The alx1
  and erg genes play both roles, but the ets1 gene ( 9 ) is used in these gene
  batteries only as the A driver"].
• Interpretation by the authors: PMID:18413610
• Not shown in the cached text: a morphological (skeleton-minus) phenotype for
  erg MASO in S. purpuratus. The skeleton-minus panels of Fig. 3 are for tbr,
  hex, tgif, ets1 and alx1; erg's effects in Oliveri 2008 are at the level of
  transcript changes (Fig. S3, Table S1). No cis-regulatory analysis of an
  Erg-dependent module is cached, so all Sp evidence for Erg activity is
  perturbation-level (IMP), not direct (IDA).

Corroboration from Lytechinus variegatus (not the reviewed gene product)

• EMT sub-circuits: PMID:24598159 and PMID:24598159. This confirms the erg -> hex linkage in a second species and
  adds an EMT requirement for erg in L. variegatus; it is not used as the
  primary basis for an S. purpuratus annotation.

Curation decisions (see the ai-review.yaml)

• Electronic rows: the IBA/InterPro/UniRule TF terms (GO:0000981, GO:0003700,
  GO:0043565, nucleus, regulation of transcription by RNA pol II) are consistent
  with an ETS-domain factor whose perturbation depresses its targets; ACCEPT.
  Generic GO:0003677 DNA binding -> MODIFY to GO:0043565; GO:0006351
  (DNA-templated transcription, UniRule) -> MODIFY to the regulation term, since
  a sequence-specific TF regulates transcription rather than performing it;
  GO:0006355 and GO:0030154 -> KEEP_AS_NON_CORE as generic parents.
• NEW (all IMP, PMID:18413610): GO:0045944 positive regulation of transcription
  by RNA polymerase II (erg MASO depresses hex and the differentiation genes it
  drives); GO:0001710 mesodermal cell fate commitment (erg-hex feedback loop
  locks down the skeletogenic mesenchyme regulatory state); GO:0070169 positive
  regulation of biomineral tissue development (erg is an A/B feed-forward driver
  of the skeletogenic differentiation gene battery).
• Not proposed: GO:0001228 activator activity (no cis-regulatory/direct assay in
  S. purpuratus; the positive sign is inferred from perturbation only, so the
  sign-neutral GO:0000981 is kept as MF); positive regulation of EMT (only Lv
  evidence); any NSM-specific process term (expression only).
• No GO-CAM contains this gene (gocams/index.tsv has no Q6R7X7 entry).