ID1-4 (Inhibitor of DNA-binding) are members of the helix-loop-helix family of proteins that lack the basic amino acids responsible for DNA binding in basic HLH proteins. HLH domain-mediated heterodimerization of an ID protein with a basic HLH protein therefore acts as a natural dominant negative inhibitor of bHLH function by preventing DNA binding (Massari and Murre, 2000). ID proteins primarily interact with members of the E family of proteins, including E12, E47, HEB and E2-2, but also interact with other bHLH proteins. ID proteins promote cell cycle progression and cell migration, and restrict cellular senescence and the differentiation of a number of progenitor cell types, including oligodendrocytes (reviewed in Perk et al, 2005; Ling et al, 2014). ID1 and ID3 proteins also have established roles in hematopoiesis (Nogueira et al, 2000; Rivera and Murre, 2001; Hong et al, 2011; Zhao et al, 2016).
ID1 and ID3 gene expression is activated by the binding of CREB1 to CRE sites in the promoter. CREB recruits transcriptional co-activators p300 and CBP in a CREB S133 phosphorylation-dependent manner (reviewed in Shaywitz and Greenberg, 1999). ID1 and ID3 gene activation also depends on the CREB1-dependent recruitment of LYL1, a basic helix-loop-helix transcription factor with roles in cell proliferation and differentiation. The N-terminal domain of LYL1 interacts with the Q2 and KID domains of CREB1 in a manner that does not require CREB1 S133 phosphorylation (San Marina et al, 2008).