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 the major binding partner of Id proteins in pluripotent cells as 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 nonpermissive 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.

Transcriptional-Regulatory Convergence Across Functional MDD Risk Variants Identified by Massively Parallel Reporter Assays

“…Functional SNP overrepresentation of SREBF motifs is consistent with high expression of these TFs in N2as and related neuroblastomas 82,83 . A second group of transcription factors included three TFs involved in neural lineage commitment/development: TCF3 84,85 , EOMES, and NR2F1 86 (6,4, and 3 SNPs, respectively). Altogether, functional SNP enrichment for these TFs' motifs bolster our confidence in this approach, as a) detected variation involves TFs known to be expressed in N2As (SREBF); b) functional variation involves TFs with roles in developing CNS, where disease variants likely act; and c) that the single-best characterized trigger of MDD (stress) is reflected in enrichment of alterations to NR3C1 motifs.…”

Transcriptional-regulatory convergence across functional MDD risk variants identified by massively parallel reporter assays

“…Functional SNP overrepresentation of SREBF motifs is consistent with high expression of these TFs in N2as and related neuroblastomas [ 98 , 99 ]. A second group of transcription factors included three TFs involved in neural lineage commitment/development: TCF3 [ 100 , 101 ], EOMES, and NR2F1 [ 102 ] (6, 4, and 3 SNPs, respectively). Altogether, functional SNP enrichment for these TFs’ motifs bolster our confidence in this approach, as (a) detected variation involves TFs known to be expressed in N2As ( SREBF ); (b) functional variation involves TFs with roles in developing CNS, where disease variants likely act; and (c) that the single-best characterized trigger of MDD (stress) is reflected in enrichment of alterations to NR3C1 motifs.…”

Cadherins in early neural development

“…What regulates the changes in cadherin expression that enable efficient differentiation? As discussed above, inhibition of BMP signalling is a key event that triggers neural differentiation [79,82,83,87]. BMP also maintains high levels of E-cadherin in pluripotent cells [186].…”

“…Neuroepithelial precursor cells can be derived by directed differentiation from mouse embryonic stem cells (ESCs) [68], human ESCs [69,70], and induced pluripotent stem cells (iPSCs) [71] by culture in basal medium with no exogenous growth factors [72]. Transcription factors that drive the formation of the anterior neuroectoderm include Sox2 [73,74], Zfp521 [75], Pou3f1/Oct6 [76], Sip1 [77], FoxD4 [78], and the homodimerised form of E2A [79]. It is flanked on either side by the neural plate border and non-neural ectoderm.…”