scholarly journals Cis-regulatory dissection of cone development reveals a broad role for Otx2 and Oc transcription factors

Development ◽  
2021 ◽  
Vol 148 (9) ◽  
Author(s):  
Nicolas Lonfat ◽  
Su Wang ◽  
ChangHee Lee ◽  
Mauricio Garcia ◽  
Jiho Choi ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Horizontal Cell ◽  
Cell Types ◽  
Regulatory Modules ◽  
Daughter Cells ◽  
Genome Wide ◽  
Cone Development ◽  
The Many ◽  
And Function ◽  
Broad Role

ABSTRACT The vertebrate retina is generated by retinal progenitor cells (RPCs), which produce >100 cell types. Although some RPCs produce many cell types, other RPCs produce restricted types of daughter cells, such as a cone photoreceptor and a horizontal cell (HC). We used genome-wide assays of chromatin structure to compare the profiles of a restricted cone/HC RPC and those of other RPCs in chicks. These data nominated regions of regulatory activity, which were tested in tissue, leading to the identification of many cis-regulatory modules (CRMs) active in cone/HC RPCs and developing cones. Two transcription factors, Otx2 and Oc1, were found to bind to many of these CRMs, including those near genes important for cone development and function, and their binding sites were required for activity. We also found that Otx2 has a predicted autoregulatory CRM. These results suggest that Otx2, Oc1 and possibly other Onecut proteins have a broad role in coordinating cone development and function. The many newly discovered CRMs for cones are potentially useful reagents for gene therapy of cone diseases.

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

2020 ◽  
Author(s):  
Nicolas Lonfat ◽  
Su Wang ◽  
ChangHee Lee ◽  
Jiho Choi ◽  
Peter J. Park ◽  
...  
Keyword(s):  
Temporal Order ◽  
Horizontal Cell ◽  
Cell Types ◽  
Retinal Diseases ◽  
Cone Photoreceptor ◽  
Regulatory Modules ◽  
Daughter Cells ◽  
Genome Wide ◽  
Cone Development ◽  
Photoreceptor Development

AbstractThe 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.

scholarly journals Genome-wide identification and characterisation of HOT regions in the human genome

2016 ◽  
Author(s):  
Hao Li ◽  
Feng Liu ◽  
Chao Ren ◽  
Xiaochen Bo ◽  
Wenjie Shu
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Embryonic Stem Cells ◽  
Epigenetic Regulation ◽  
Human Cell ◽  
Embryonic Stem ◽  
Cell Types ◽  
Genome Wide ◽  
Development And Differentiation ◽  
Epigenetic Analysis

AbstractHOT (high-occupancy target) regions, which are bound by a surprisingly large number of transcription factors, are considered to be among the most intriguing findings of recent years. An improved understanding of the roles that HOT regions play in biology would be afforded by knowing the constellation of factors that constitute these domains and by identifying HOT regions across the spectrum of human cell types. We characterised and validated HOT regions in embryonic stem cells (ESCs) and produced a catalogue of HOT regions in a broad range of human cell types. We found that HOT regions are associated with genes that control and define the developmental processes of the respective cell and tissue types. We also showed evidence of the developmental persistence of HOT regions at primitive enhancers and demonstrate unique signatures of HOT regions that distinguish them from typical enhancers and super-enhancers. Finally, we performed an epigenetic analysis to reveal the dynamic epigenetic regulation of HOT regions upon H1 differentiation. Taken together, our results provide a resource for the functional exploration of HOT regions and extend our understanding of the key roles of HOT regions in development and differentiation.

scholarly journals Bi-fated tendon-to-bone attachment cells are regulated by shared enhancers and KLF transcription factors

2020 ◽  
Author(s):  
Shiri Kult ◽  
Tsviya Olender ◽  
Marco Osterwalder ◽  
Sharon Krief ◽  
Ronnie Blecher-Gonen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Single Molecule ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Regulatory Elements ◽  
Transcriptional Enhancer ◽  
Molecular Identity ◽  
And Function

AbstractThe connection between different tissues is vital for the development and function of any organs and systems. In the musculoskeletal system, the attachment of elastic tendons to stiff bones poses a mechanical challenge that is solved by the formation of a transitional tissue, which allows the transfer of muscle forces to the skeleton without tearing. Here, we show that tendon-to-bone attachment cells are bi-fated, activating a mixture of chondrocyte and tenocyte transcriptomes, which is regulated by sharing regulatory elements with these cells and by Krüppel-like factors transcription factors (KLF).To uncover the molecular identity of attachment cells, we first applied high-throughput RNA sequencing to murine humeral attachment cells. The results, which were validated by in situ hybridization and single-molecule in situ hybridization, reveal that attachment cells express hundreds of chondrogenic and tenogenic genes. In search for the underlying mechanism allowing these cells to express these genes, we performed ATAC sequencing and found that attachment cells share a significant fraction of accessible intergenic chromatin areas with either tenocytes or chondrocytes. Epigenomic analysis further revealed transcriptional enhancer signatures for the majority of these regions. We then examined a subset of these regions using transgenic mouse enhancer reporter. Results verified the shared activity of some of these enhancers, supporting the possibility that the transcriptome of attachment cells is regulated by enhancers with shared activities in tenocytes or chondrocytes. Finally, integrative chromatin and motif analyses, as well as the transcriptome data, indicated that KLFs are regulators of attachment cells. Indeed, blocking the expression of Klf2 and Klf4 in the developing limb mesenchyme led to abnormal differentiation of attachment cells, establishing these factors as key regulators of the fate of these cells.In summary, our findings show how the molecular identity of bi-fated attachment cells enables the formation of the unique transitional tissue that connect tendon to bone. More broadly, we show how mixing the transcriptomes of two cell types through shared enhancers and a dedicated set of transcription factors can lead to the formation of a new cell fate that connects them.

Transcriptional Control of Lung Morphogenesis

2007 ◽  
Vol 87 (1) ◽  
pp. 219-244 ◽  
Author(s):  
Yutaka Maeda ◽  
Vrushank Davé ◽  
Jeffrey A. Whitsett
Keyword(s):  
Transcription Factors ◽  
Transcriptional Control ◽  
Family Members ◽  
Cell Types ◽  
Branching Morphogenesis ◽  
Early Embryo ◽  
Normal Lung ◽  
Thyroid Transcription Factor 1 ◽  
Lung Morphogenesis ◽  
And Function

The vertebrate lung consists of multiple cell types that are derived primarily from endodermal and mesodermal compartments of the early embryo. The process of pulmonary organogenesis requires the generation of precise signaling centers that are linked to transcriptional programs that, in turn, regulate cell numbers, differentiation, and behavior, as branching morphogenesis and alveolarization proceed. This review summarizes knowledge regarding the expression and proposed roles of transcription factors influencing lung formation and function with particular focus on knowledge derived from the study of the mouse. A group of transcription factors active in the endodermally derived cells of the developing lung tubules, including thyroid transcription factor-1 (TTF-1), β-catenin, Forkhead orthologs (FOX), GATA, SOX, and ETS family members are required for normal lung morphogenesis and function. In contrast, a group of distinct proteins, including FOXF1, POD1, GLI, and HOX family members, play important roles in the developing lung mesenchyme, from which pulmonary vessels and bronchial smooth muscle develop. Lung formation is dependent on reciprocal signaling among cells of both endodermal and mesenchymal compartments that instruct transcriptional processes mediating lung formation and adaptation to breathing after birth.

scholarly journals Identification and functional characterization of circular RNAs in pericytes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Glaser ◽  
A.W Heumueller ◽  
M Klangwart ◽  
A Wiederer ◽  
D John ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factors ◽  
Cell Biology ◽  
Functional Characterization ◽  
Cell Types ◽  
Circular Rna ◽  
Circular Rnas ◽  
Funding Source ◽  
Factor Screening ◽  
And Function

Abstract Background Circular RNAs (circRNAs) are generated by back-splicing. They are known to be robustly expressed in a variety of mammalian cell types and organism and have been reported to influence cell biology by acting e.g. as microRNA sponges or regulating host gene expression. Recently, our group reported functionally relevant circRNA expression in endothelial cells. Despite their important role in the cardiovascular system, the expression and function of circRNAs in pericytes is not well studied. Pericytes are perivascular mural cells, important for vessel maturation and endothelial barrier function. Their recruitment towards endothelial cells is mainly meditated by platelet-derived growth factor (PDGF) signaling. However, a more precise understanding of the regulation of pericyte differentiation and survival is necessary. Objective Here, we analyse circRNA expression in pericytes and demonstrate biological relevance of the hypoxia regulated circular RNA PLOD2 (cPLOD2). Methods and results Using RNA Sequencing in ribosomal depleted RNA we characterized the expression of circRNAs in human pericytes under normoxic and hypoxic (1% O2, 48h) conditions. We identified several circular RNAs being regulated upon hypoxia. The identified circular RNAs demonstrated resistance towards RNase-R digestion and lacking of poly-adenylation. Some of them were found to be localized and in the cytosol, whereas others also occur in the nucleus of the cells. Especially cPLOD2 raised our attention since it is significantly upregulated and robustly expressed upon hypoxia. Silencing cPLOD2 by siRNA resulted in significant de-differentiation of pericytes that went along with a loss of cell viability. Mechanistically, transcription factor screening assays revealed that silencing of cPLOD2 enhances the activity of the transcription factors ELK1/SRF, which have been documented to result in de-differentiation of smooth muscle cells. Conclusion Here we characterize the expression pattern of circRNAs in human primary pericytes. Among others, cPLOD2 significantly regulates pericyte function. Our results indicate hypoxia as a major regulator of circRNA expression in pericytes and show that circRNAs are capable of regulating pericyte function by modulating activity of transcription factors. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Deutsche Forschungsgesellschaft (DFG) - SFB834; Deutsche Gesellschaft für Herz-Kreislaufforschung (DZHK)

Hox transcription factors: an overview of multi-step regulators of gene expression

2018 ◽  
Vol 62 (11-12) ◽  
pp. 723-732 ◽  
Author(s):  
Julie Carnesecchi ◽  
Pedro B. Pinto ◽  
Ingrid Lohmann
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cell Fates ◽  
Hox Proteins ◽  
Regulatory Modules ◽  
Genome Wide ◽  
Transcription Complexes ◽  
Regulatory Functions

Hox transcription factors (TFs) function as key determinants in the specification of cell fates during development. They do so by triggering entire morphogenetic cascades through the activation of specific target genes. In contrast to their fundamental role in development, the molecular mechanisms employed by Hox TFs are still poorly understood. In recent years, a new picture has emerged regarding the function of Hox proteins in gene regulation. Initial studies have primarily focused on understanding how Hox TFs recognize and bind specific enhancers to activate defined Hox targets. However, genome-wide studies on the interactions and dynamics of Hox proteins have revealed a more elaborate function of the Hox factors. It is now known that Hox proteins are involved in several steps of gene expression with potential regulatory functions in the modification of the chromatin landscape and its accessibility, recognition and activation of specific cis-regulatory modules, assembly and activation of promoter transcription complexes and mRNA processing. In the coming years, the characterization of the molecular activity of Hox TFs in these mechanisms will greatly contribute to our general understanding of Hox activity.

scholarly journals Quantitative occupancy of myriad transcription factors from one DNase experiment enables efficient comparisons across conditions

2020 ◽  
Author(s):  
Kaixuan Luo ◽  
Jianling Zhong ◽  
Alexias Safi ◽  
Linda K. Hong ◽  
Alok K. Tewari ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Chromatin Immunoprecipitation ◽  
Cost Effective ◽  
Cell Types ◽  
Hierarchical Regression ◽  
Bayesian Hierarchical ◽  
Genome Wide ◽  
Regression Framework ◽  
Quantitative Changes ◽  
Using Data

AbstractOver a thousand different transcription factors (TFs) bind with varying occupancy across the human genome. Chromatin immunoprecipitation (ChIP) can assay occupancy genome-wide, but only one TF at a time, limiting our ability to comprehensively observe the TF occupancy landscape, let alone quantify how it changes across conditions. We developed TOP, a Bayesian hierarchical regression framework, to profile genome-wide quantitative occupancy of numerous TFs using data from a single DNase-seq experiment. TOP is supervised, and its hierarchical structure allows it to predict the occupancy of any sequence-specific TF, even those never assayed with ChIP. We used TOP to profile the quantitative occupancy of nearly 1500 human TF motifs, and examined how their occupancies changed genome-wide in multiple contexts: across 178 cell types, over 12 hours of exposure to different hormones, and across the genetic backgrounds of 70 individuals. TOP enables cost-effective exploration of quantitative changes in the landscape of TF binding.

scholarly journals Comparing the epigenetic landscape in myonuclei purified with a PCM1 antibody from a fast/glycolytic and a slow/oxidative muscle

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009907
Author(s):  
Mads Bengtsen ◽  
Ivan Myhre Winje ◽  
Einar Eftestøl ◽  
Johannes Landskron ◽  
Chengyi Sun ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Binding Sites ◽  
Association Studies ◽  
Cell Types ◽  
Specific Marker ◽  
Fiber Types ◽  
Epigenetic Landscape ◽  
Genome Wide ◽  
A Genome ◽  
Pericentriolar Material

Muscle cells have different phenotypes adapted to different usage, and can be grossly divided into fast/glycolytic and slow/oxidative types. While most muscles contain a mixture of such fiber types, we aimed at providing a genome-wide analysis of the epigenetic landscape by ChIP-Seq in two muscle extremes, the fast/glycolytic extensor digitorum longus (EDL) and slow/oxidative soleus muscles. Muscle is a heterogeneous tissue where up to 60% of the nuclei can be of a different origin. Since cellular homogeneity is critical in epigenome-wide association studies we developed a new method for purifying skeletal muscle nuclei from whole tissue, based on the nuclear envelope protein Pericentriolar material 1 (PCM1) being a specific marker for myonuclei. Using antibody labelling and a magnetic-assisted sorting approach, we were able to sort out myonuclei with 95% purity in muscles from mice, rats and humans. The sorting eliminated influence from the other cell types in the tissue and improved the myo-specific signal. A genome-wide comparison of the epigenetic landscape in EDL and soleus reflected the differences in the functional properties of the two muscles, and revealed distinct regulatory programs involving distal enhancers, including a glycolytic super-enhancer in the EDL. The two muscles were also regulated by different sets of transcription factors; e.g. in soleus, binding sites for MEF2C, NFATC2 and PPARA were enriched, while in EDL MYOD1 and SIX1 binding sites were found to be overrepresented. In addition, more novel transcription factors for muscle regulation such as members of the MAF family, ZFX and ZBTB14 were identified.

scholarly journals Specification of diverse cell types during early neurogenesis of the mouse cerebellum

2018 ◽  
Author(s):  
John W. Wizeman ◽  
Qiuxia Guo ◽  
Elliot Wilion ◽  
James Y.H. Li
Keyword(s):  
Cell Fate ◽  
Developmental Trajectories ◽  
Ventricular Zone ◽  
Cell Types ◽  
Genome Wide ◽  
Integral Role ◽  
Cerebellar Cell ◽  
Early Neurogenesis ◽  
And Function ◽  
Developing Cerebellum

SUMMARYWe applied single-cell RNA sequencing to profile genome-wide gene expression in about 9,400 individual cerebellar cells from the mouse embryo at embryonic day 13.5. Reiterative clustering identified the major cerebellar cell types and subpopulations of different lineages. Through pseudotemporal ordering to reconstruct developmental trajectories, we identified novel transcriptional programs controlling cell fate specification of populations arising from the ventricular zone and the anterior rhombic lip, two distinct germinal zones of the embryonic cerebellum. Together, our data revealed cell-specific markers for studying the cerebellum, important specification decisions, and a number of previously unknown subpopulations that may play an integral role in the formation and function of the cerebellum. Importantly, we identified a potential mechanism of vermis formation, which is affected by multiple congenital cerebellar defects. Our findings will facilitate new discovery by providing insights into the molecular and cell type diversity in the developing cerebellum.

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