Biology subjects

Lonfat, N.

Publications and source records attributed to Lonfat, N..

3 recordsLinked to original sources

bioRxiv2020

Otx2 and Oc1 directly regulate the transcriptional program of cone photoreceptor development

The vertebrate retina is a highly organized structure of approximately 110 cell types. Retinal progenitor cells (RPCs) produce these cell types in a temporal order that is highly conserved. While some RPCs produce many cell types, some terminally dividing RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). Here, we compared the transcriptomes and chromatin profiles of such a restricted cone/HC RPC with those of other RPCs. We identified many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. We then showed that Otx2 and Oc1 directly regulate the activity of multiple CRMs genome-wide, including near genes important for cone development, such as Rxrg and Neurod1. In addition, we found that Otx2 regulates itself. These results suggest that Otx2 and Oc1 have a broader role than previously appreciated, and deepen our understanding of retinal development, which may benefit therapies for retinal diseases.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗

bioRxiv2019

Cell type- and stage-specific expression of Otx2 is coordinated by a cohort of transcription factors and multiple cis-regulatory modules in the retina

Transcription factors (TFs) are often used repeatedly during development and homeostasis to control distinct processes in the same and/or different cellular contexts. Considering the limited number of TFs in the genome and the tremendous number of events that need to be regulated, re-use of TFs is an advantageous strategy. However, the mechanisms that control the activation of TFs in different cell types and at different stages of development remain unclear. The neural retina serves as a model of the development of a complex tissue. We used this system to analyze how expression of the homeobox TF, Orthodenticle homeobox 2 (Otx2), is regulated in a cell type- and stage-specific manner during retinogenesis. We identified seven Otx2 cis-regulatory modules (CRMs), among which the O5, O7 and O9 CRMs mark three distinct cellular contexts of Otx2 expression. These include mature bipolar interneurons, photoreceptors, and retinal progenitor/precursor cells. We discovered that Otx2, Crx and Sox2, which are well-known TFs regulating retinal development, bind to and activate the O5, O7 or O9 CRMs respectively. The chromatin status of these three CRMs was found to be distinct in vivo in different retinal cell types and at different stages, as revealed by ATAC-seq and DNase-seq analyses. We conclude that retinal cells utilize a cohort of TFs with different expression patterns, and multiple CRMs with different chromatin configurations, to precisely regulate the expression of Otx2 in a cell type- and stage-specific manner in the retina.

developmental biology↗

bioRxiv2019

Enhancer transcription identifies cis-regulatory elements for photoreceptor cell types

Identification of the cis-regulatory elements (CREs) that regulate gene expression in specific cell types is critical for defining the gene regulatory networks (GRNs) that control normal physiology and disease states. We previously utilized non-coding RNA (ncRNA) profiling to define CREs that comprise a GRN in the adult mouse heart1. Here, we applied ncRNA profiling to the mouse retina in the presence and absence of Nrl, a rod photoreceptor-specific transcription factor required for rod versus cone photoreceptor cell fate. Differential expression of Nrl-dependent ncRNAs positively correlated with differential expression of Nrl-dependent local genes. Two distinct Nrl-dependent regulatory networks were discerned in parallel: Nrl-activated ncRNAs were enriched for accessible chromatin in rods but not cones whereas Nrl-repressed ncRNAs were enriched for accessible chromatin in cones but not rods. Furthermore, differential Nrl-dependent ncRNA expression levels quantitatively correlated with photoreceptor cell type-specific ATAC-seq read density. Direct assessment of Nrl-dependent ncRNA-defined loci identified functional cone photoreceptor CREs. This work supports differential ncRNA profiling as a platform for identifying context-specific regulatory elements and provides insight into the networks that define photoreceptor cell types.

molecular biology↗