The transcription factor E2A drives neural differentiation in pluripotent cells

Abstract

The intrinsic mechanisms that link extracellular signalling to the onset of neural differentiation are not well understood. In pluripotent mouse cells, BMP blocks entry into the neural lineage via transcriptional upregulation of Inhibitor of Differentiation (Id) factors. We have previously identified that the major binding partner of Id proteins in pluripotent cells is the basic helix-loop-helix (bHLH) transcription factor (TF), E2A. Id1 can prevent E2A from forming heterodimers with bHLH TFs or from forming homodimers. Here, we show that overexpression of a forced E2A homodimer is sufficient to drive robust neural commitment in pluripotent cells, even under non-permissive conditions. Conversely, we find that E2A null cells display a defect in their neural differentiation capacity. E2A acts as an upstream activator of neural lineage genes, including Sox1 and Foxd4, and as a repressor of Nodal signalling. Our results suggest a crucial role for E2A in establishing neural lineage commitment in pluripotent cells.

ID1 and CEBPA Coordinate Epidermal Progenitor Cell Differentiation

“…We were not able to identify additional heterodimerizing bHLH partners using cultured epidermal progenitors (Figure 5), suggesting that TCF3 could regulate epidermal transcriptional targets as a TCF-TCF homodimer. Homodimerization of TCF3 has been demonstrated to control cell fate in pluripotent stem cells as well as in the B-cell and myogenic lineage (Neuhold and Wold, 1993; Rao et al, 2020; Shen and Kadesch, 1995), and homodimers are more sensitive to ID1 inhibition compared to their TCF3-bHLH counterpart (Neuhold and Wold, 1993), increasing regulatory complexity in predicting the downstream transcriptional effects of bHLH activity. It would be interesting to functionally delineate the role of TCF dimerization in epidermal progenitors.…”

MTG16 (CBFA2T3) regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors

“…Furthermore, enteroendocrine cell lineage commitment is dependent on a cascade of type II bHLH transcription factors 107,108 , including NEUROG3 and its downstream target NEUROD1 104,109 , which is known to heterodimerize with E12 and E47 in other systems 110 . Additionally, E2A homodimers promote neural lineage commitment by inducing transcription of Neurog1-3 in neurogenesis 47,49 . Thus, we hypothesized that MTG16 attenuated enteroendocrine lineage allocation by repressing E protein-mediated transcription of enteroendocrine bHLH transcription factors.…”

“…Enteroendocrine cell lineage commitment is dependent on a cascade of type II bHLH transcription factors including NEUROG3 and its downstream target NEUROD1 (71). E proteins are known to induce transcription of Neurog1-3 in neurogenesis (30, 32), and NEUROD1 heterodimerizes with E proteins in other systems (72). Although E proteins have been detected in SI stem cells and adenomas (48), E protein function in colon homeostasis remained unknown.…”

“…Enteroendocrine cell lineage commitment is dependent on a cascade of type II bHLH transcription factors including NEUROG3 and its downstream target NEUROD1 (71). E proteins are known to induce transcription of Neurog1-3 in neurogenesis (30,32), and NEUROD1…”

“…The class I bHLH transcription factors, also known as E proteins because they bind to consensus Ephrussi box (E box) DNA sequences, are E12 and E47 (splice variants of E2A), HEB, and E2-2 28,38,40 . However, the functions of E proteins have mainly been described outside of the colon 40,[42][43][44][45][46][47][48][49] .…”