Highly specific interactions between bHLH transcription factors and chromatin during retina development

Abstract

Basic helix-loop-helix (bHLH) transcription factors such as atonal homolog 5 (ATH5) and neurogenin 2 (NGN2) determine crucial events in retinogenesis. Using chromatin immunoprecipitation, we demonstrate that their interactions with target promoters undergo dynamic changes as development proceeds in the chick embryo. Chick ATH5 associates with its own promoter and with the promoter of the β3 nicotinic receptor specifically in retinal ganglion cells and their precursors. NGN2 binds to the ATH5 promoter in retina but not in optic tectum, suggesting that interactions between bHLH factors and chromatin are highly tissue specific. The transcriptional activations of both promoters correlate with dimethylation of lysine 4 on histone H3. Inactivation of the ATH5 promoter in differentiated neurons is accompanied by replication-independent chromatin de-methylation. This report is one of the first demonstrations of correlation between gene expression, binding of transcription factors and chromatin modification in a developing neural tissue.

Conserved regulation of Math5 and Math1 revealed by Math5-GFP transgenes

“…First, the distal conserved region of Math5, which contains a retinal enhancer (Riesenberg et al, 2007) does not align to the Math1 enhancer sequence, suggesting that the retinal enhancer for Math5 may have been added after these genes duplicated and diverged, or it was subsequently lost from Math1. Second, the Math1 autoregulatory E-box, that maintains expression in the dorsal spinal cord, and the Ath5 E1 E-box, required for maintenance of retinal expression in frog and chick (Skowronska-Krawczyk et al, 2004;Hutcheson et al, 2005), align to one another, providing one explanation for Math1 cross-regulation of our transgenes. Finally, we demonstrate functional Pax6 binding sites for both Math5 and Math1, which could account for the similar regulation of Math5-GFP and Math1 by this factor.…”

Pea3 expression is regulated by FGF signaling in developing retina

“…The proneural ath5 gene is a bHLH transcription factor that has been shown in several species to be necessary and sufficient for ganglion cell differentiation (Brown et al, 2001;Hutcheson et al, 2005;Kanekar et al, 1997;Liu et al, 2001;Kay et al, 2005;Ma et al, 2004a,b;Masai et al, 2005;Skowronska-Krawczyk et al, 2004;Wang et al, 2001;Xie et al, 2004). To better understand the potential role of Pea3 in ganglion cell differentiation, we asked whether the chick ath homologue, Cath5 (Liu et al, 2001) is regulated by FGF similarly to Pea3 regulation.…”

Delayed neurogenesis with respect to eye growth shapes the pigeon retina for high visual acuity

“…The transcription factor (TF) atonal homolog 7 (ATOH7; also known as ATH5) is required for the production of RGCs in vertebrates (Brown et al, 2001;Del Bene et al, 2007;Kanekar et al, 1997;Kay et al, 2001;Liu et al, 2001;Matter-Sadzinski et al, 2001;Wang et al, 2001) and the transcriptional network underlying the production of RGCs is well conserved between mouse, chicken and fish (Brown et al, 1998(Brown et al, , 2001Hufnagel et al, 2010;Kay et al, 2001;Matter-Sadzinski et al, 2001Sinn et al, 2014;Skowronska-Krawczyk et al, 2004). However, whereas the majority of the ATOH7-expressing cells enter the RGC lineage in the chick, only a few percent produce RGCs in the mouse (Prasov and Glaser, 2012;Skowronska-Krawczyk et al, 2009;Yang et al, 2003).…”