Specification of Neuropeptide Cell Identity by the Integration of Retrograde BMP Signaling and a Combinatorial Transcription Factor Code

Introduction: The Renin-Angiotensin-System is essential to maintain blood pressure and fluid electrolyte homeostasis. Because precise regulation of expression and release of renin is critical for survival, understanding the molecular regulation of the renin cell identity is a vital area of study. Advances in epigenetics have enabled finer dissection of chromatin factors which maintain the identity of the renin cell. By studying genes with heightened accessibility profiles that are unique to the JG cell, we now have the capacity to unravel the determinants of the renin cell identity. Hypothesis: That transcription factors central to the governance of renin cell identity can be identified through the Assay for Transposase Accessible Chromatin (ATAC-seq) differential accessibility analysis. Methods: Native renin cell ATAC-seq was compared to existing ENCODE ATAC-seq datasets from 40 other cell types to define regions/peaks which characterize the JG program. Peaks with high intensity and ≥2-fold increase in signal were selected for Motif analysis to search for transcription factors (TFs) whose consensus sequence is enriched in those regions. Identified TFs were then selected for validation by in-situ hybridization and conditional deletion in renin cells. Results: 1) The Mef2c transcription factor was identified as having a consensus sequence in regulatory regions unique to the JG cell. It has clear expression in RNA-seq of renin cells (65 transcripts per million, n=3) and a predicted binding site in the renin gene. These results were validated by in-situ hybridization where signal localized at the JG area was detected in concordance with our in-silico results. 2) We generated Mef2c conditional knockout animals using our Ren1d-Cre mouse to study the effect in renin expression and identity. These mice displayed reduced renin immunostaining at the JG area and a 40% reduction in renin mRNA expression by qPCR from kidney cortices relative to wild-type (n=2, preliminary data). Conclusions: Our studies identified Mef2c as a TF target which likely has an essential role in maintaining and preserving renin cell identity. Experiments involving transcriptomics and epigenomics are ongoing to understand the changes wrought by Mef2c deletion in renin cells.

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BMP signaling patterns the dorsal and intermediate neural tube via regulation of homeobox and helix-loop-helix transcription factors

Development ◽

10.1242/dev.129.10.2459 ◽

2002 ◽

Vol 129 (10) ◽

pp. 2459-2472 ◽

Cited By ~ 15

Author(s):

John R. Timmer ◽

Charlotte Wang ◽

Lee Niswander

Keyword(s):

Transcription Factors ◽

Neural Tube ◽

Transforming Growth Factor ◽

Cell Types ◽

Neural Cell ◽

Bmp Signaling ◽

Expression Domain ◽

Cell Identity ◽

Dorsoventral Axis ◽

Helix Loop Helix

In the spinal neural tube, populations of neuronal precursors that express a unique combination of transcription factors give rise to specific classes of neurons at precise locations along the dorsoventral axis. Understanding the patterning mechanisms that generate restricted gene expression along the dorsoventral axis is therefore crucial to understanding the creation of diverse neural cell types. Bone morphogenetic proteins (BMPs) and other transforming growth factor β (TGFβ) proteins are expressed by the dorsal-most cells of the neural tube (the roofplate) and surrounding tissues, and evidence indicates that they play a role in assigning cell identity. We have manipulated the level of BMP signaling in the chicken neural tube to show that BMPs provide patterning information to both dorsal and intermediate cells. BMP regulation of the expression boundaries of the homeobox proteins Pax6, Dbx2 and Msx1 generates precursor populations with distinct developmental potentials. Within the resulting populations, thresholds of BMP act to set expression domain boundaries of developmental regulators of the homeobox and basic helix-loop-helix (bHLH) families, ultimately leading to the generation of a diversity of differentiated neural cell types. This evidence strongly suggests that BMPs are the key regulators of dorsal cell identity in the spinal neural tube.

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Intimate Relationship Between TGF-β/BMP Signaling and Runt Domain Transcription Factor, PEBP2/CBF

The Journal of Bone and Joint Surgery (American) ◽

10.2106/00004623-200100001-00007 ◽

2001 ◽

Vol 83 ◽

pp. S1-48–S1–55 ◽

Cited By ~ 6

Author(s):

Suk-Chul Bae ◽

Kycong-Sook Lee ◽

Yu-Wen Zhang ◽

Yoshiaki Ito

Keyword(s):

Transcription Factor ◽

Intimate Relationship ◽

Bmp Signaling ◽

Runt Domain

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The ETS-transcription factor Pointed is sufficient to regulate the posterior fate of the follicular epithelium

Development ◽

10.1242/dev.189787 ◽

2020 ◽

Vol 147 (22) ◽

pp. dev189787

Author(s):

Cody A. Stevens ◽

Nicole T. Revaitis ◽

Rumkan Caur ◽

Nir Yakoby

Keyword(s):

Transcription Factor ◽

Growth Factor Receptor ◽

Bmp Signaling ◽

Janus Kinase ◽

Follicle Cells ◽

Follicular Epithelium ◽

T Box ◽

Border Cell ◽

Morphogenetic Protein ◽

Ets Transcription Factor

ABSTRACTThe Janus-kinase/signal transducer and activator of transcription (JAK/STAT) pathway regulates the anterior posterior axis of the Drosophila follicle cells. In the anterior, it activates the bone morphogenetic protein (BMP) signaling pathway through expression of the BMP ligand decapentaplegic (dpp). In the posterior, JAK/STAT works with the epidermal growth factor receptor (EGFR) pathway to express the T-box transcription factor midline (mid). Although MID is necessary for establishing the posterior fate of the egg chamber, we show that it is not sufficient to determine a posterior fate. The ETS-transcription factor pointed (pnt) is expressed in an overlapping domain to mid in the follicle cells. This study shows that pnt is upstream of mid and that it is sufficient to induce a posterior fate in the anterior end, which is characterized by the induction of mid, the prevention of the stretched cells formation and the abrogation of border cell migration. We demonstrate that the anterior BMP signaling is abolished by PNT through dpp repression. However, ectopic DPP cannot rescue the anterior fate formation, suggesting additional targets of PNT participate in the posterior fate determination.

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The transcription factor Zic4 acts as a transdifferentiation switch

10.1101/2021.12.22.473838 ◽

2021 ◽

Author(s):

Matthias Christian Vogg ◽

Jaroslav Ferenc ◽

Wanda Christa Buzgariu ◽

Chrystelle Perruchoud ◽

Panagiotis Papasaikas ◽

...

Keyword(s):

Cell Cycle ◽

Transcription Factor ◽

Gene Regulatory Network ◽

Cell Fate ◽

Regulatory Network ◽

Molecular Mechanisms ◽

Model System ◽

Cell Identity ◽

Transcriptional Switch ◽

Gene Regulatory

The molecular mechanisms that maintain cell identities and prevent transdifferentiation remain mysterious. Interestingly, both dedifferentiation and transdifferentiation are transiently reshuffled during regeneration. Therefore, organisms that regenerate readily offer a fruitful paradigm to investigate the regulation of cell fate stability. Here, we used Hydra as a model system and show that Zic4 silencing is sufficient to induce transdifferentiation of tentacle into foot cells. We identified a Wnt-controlled Gene Regulatory Network that controls a transcriptional switch of cell identity. Furthermore, we show that this switch also controls the re-entry into the cell cycle. Our data indicate that maintenance of cell fate by a Wnt-controlled GRN is a key mechanism during both homeostasis and regeneration.

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Transcription factor ATF4 maintains pancreatic β-cell identity during ER stress

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.94.0_2-y-e2-1 ◽

2021 ◽

Vol 94 (0) ◽

pp. 2-Y-E2-1

Author(s):

Keisuke Kitakaze ◽

Miho Oyadomari ◽

Jun Zhang ◽

Yoshimasa Hamada ◽

Yasuhiro Takenouchi ◽

...

Keyword(s):

Transcription Factor ◽

Er Stress ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Identity

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The transcriptional corepressor CTBP-1 acts with the SOX family transcription factor EGL-13 to maintain AIA interneuron cell identity in C. elegans

10.1101/2021.07.28.454018 ◽

2021 ◽

Author(s):

Josh Saul ◽

Takashi Hirose ◽

Robert Horvitz

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Cell Fate ◽

Transcriptional Corepressor ◽

Cell Identity ◽

C Elegans ◽

Dna Binding Specificity ◽

A Cell ◽

Transcriptional Corepressors ◽

And Function

Cell identity is characterized by a distinct combination of gene expression, cell morphology and cellular function established as progenitor cells divide and differentiate. Following establishment, cell identities can be unstable and require active and continuous maintenance throughout the remaining life of a cell. Mechanisms underlying the maintenance of cell identities are incompletely understood. Here we show that the gene ctbp-1, which encodes the transcriptional corepressor C-terminal binding protein-1 (CTBP-1), is essential for the maintenance of the identities of the two AIA interneurons in the nematode Caenorhabditis elegans. ctbp-1 is not required for the establishment of the AIA cell fate but rather functions cell-autonomously and can act in older worms to maintain proper AIA gene expression, morphology and function. From a screen for suppressors of the ctbp-1 mutant phenotype, we identified the gene egl-13, which encodes a SOX family transcription factor. We found that egl-13 regulates AIA function and aspects of AIA gene expression, but not AIA morphology. We conclude that the CTBP-1 protein maintains AIA cell identity in part by utilizing EGL-13 to repress transcriptional activity in the AIAs. More generally, we propose that transcriptional corepressors like CTBP-1 might be critical factors in the maintenance of cell identities, harnessing the DNA-binding specificity of transcription factors like EGL-13 to selectively regulate gene expression in a cell-specific manner.

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