HAND2 (dHAND) notes

Automated deep research was unavailable for this review (falcon 402, OpenAI 401), so these notes
were compiled manually from cached PubMed abstracts/full texts, the UniProt record (P61296) and
QuickGO annotations of the mouse ortholog (Q61039).

Identity and molecular mechanism

• Twist-family class B bHLH transcription factor (bHLH domain aa 99-151; Pfam PF00010). Human gene
  cloned and strongly expressed in heart PMID:9878849.
• Heterodimerizes with E-proteins (E12/E47, TCF4, TCF12) and binds a subset of E-boxes; N-terminal
  activation domain [PMID:11812799 "HAND2 contains a strong transcriptional activation domain in the amino-terminal third of the protein"; "HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins"]. Homodimers form in vitro but not robustly in cells
  PMID:11812799.
• Dimer partner choice with TWIST1 is regulated by PKA/PP2A phosphorylation of helix I
  PMID:15735646.
• DNA-binding-independent activity: limb digit duplication needs only the HLH
  PMID:12070084;
  ANF activation independent of E-boxes PMID:12392994.
• Partner TFs: GATA4 (bHLH-zinc finger interaction, p300 recruitment)
  [PMID:11994297 "the bHLH domain of dHAND physically interacted with the C-terminal zinc finger domain of GATA4 forming a higher order complex"; "the bHLH domain of dHAND directly interacted with the CH3 domain of p300"];
  MEF2C PMID:15486975;
  NKX2-5 synergy on ANF PMID:12392994; PHOX2A PMID:16280598.
• p300/CBP dependence in autonomic neuron induction PMID:16145670.

Biological roles (mostly from mouse)

• Heart: right ventricle and aortic arch arteries PMID:9171826;
  with Nkx2-5 for the entire ventricular segment PMID:11784028,
  role in survival/expansion, not specification PMID:11784028.
  Cardiac neural crest: OFT alignment, SHF proliferation non-autonomously PMID:19008477.
• Adult heart disease: re-expressed in failing myocardium; drives pathological hypertrophy PMID:24161931.
• Limb: upstream of Shh in the ZPA PMID:10804186.
• Sympathetic/noradrenergic neurons [PMID:18501887; PMID:16145670]; enteric neurons PMID:17075884.
• Branchial arches downstream of endothelin-1 (PMID:9671575, cached).
• Uterus: progesterone-induced stromal Hand2 suppresses FGFs to block epithelial proliferation; required for implantation
  PMID:21330545.

Curation notes

• Module (cardiac_specification_network) annoton GO:0000981 in heart development is consistent with
  the review. Note that a subset of HAND2 activity is DNA-binding independent (co-activator-like via
  GATA4/p300), so GO:0061629 is also a core MF.
• GO:0003680 (AT-rich minor groove binding) from PMID:15486975 likely reflects the MEF2C A/T site in a
  MEF2C-HAND2 complex rather than HAND2 activity.