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

2019 ◽  
Author(s):  
Candace Chan ◽  
Nicolas Lonfat ◽  
Rong Zhao ◽  
Alexander Davis ◽  
Liang Li ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Expression Patterns ◽  
Cell Types ◽  
Retinal Cell ◽  
Cell Type ◽  
Specific Expression ◽  
Regulatory Modules ◽  
Specific Manner ◽  
A Cell

AbstractTranscription 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.

scholarly journals Cell type- and stage-specific expression of Otx2 is regulated by multiple transcription factors and cis-regulatory modules in the retina

Development ◽  
2020 ◽  
Vol 147 (14) ◽  
pp. dev187922 ◽  
Author(s):  
Candace S. Y. Chan ◽  
Nicolas Lonfat ◽  
Rong Zhao ◽  
Alexander E. Davis ◽  
Liang Li ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Expression Patterns ◽  
Cell Types ◽  
Retinal Cell ◽  
Mouse Retina ◽  
Cell Type ◽  
Specific Expression ◽  
Regulatory Modules ◽  
A Cell

ABSTRACTTranscription 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 necessary. We analyzed how the expression of the homeobox TF, orthodenticle homeobox 2 (Otx2), is regulated in a cell type- and stage-specific manner during development in the mouse retina. We identified seven Otx2 cis-regulatory modules (CRMs), among which the O5, O7 and O9 CRMs mark three distinct cellular contexts of Otx2 expression. 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. We conclude that retinal cells use a cohort of TFs with different expression patterns and multiple CRMs with different chromatin configurations to regulate the expression of Otx2 precisely.

scholarly journals Heterogeneity of Transcription Factor binding specificity models within and across cell lines

2015 ◽  
Author(s):  
Mahfuza Sharmin ◽  
Hector Corrada Bravo ◽  
Sridhar S. Hannenhalli
Keyword(s):  
Expression Patterns ◽  
Specific Interaction ◽  
Cell Types ◽  
Cell Type ◽  
Binding Interaction ◽  
Interaction Partners ◽  
A Cell ◽  
Cell Type Specific ◽  
Different Cell Types

Complex gene expression patterns are mediated by binding of transcription factors (TF) to specific genomic loci. The in vivo occupancy of a TF is, in large part, determined by the TFs DNA binding interaction partners, motivating genomic context based models of TF occupancy. However, the approaches thus far have assumed a uniform binding model to explain genome wide bound sites for a TF in a cell-type and as such heterogeneity of TF occupancy models, and the extent to which binding rules underlying a TFs occupancy are shared across cell types, has not been investigated. Here, we develop an ensemble based approach (TRISECT) to identify heterogeneous binding rules of cell-type specific TF occupancy and analyze the inter-cell-type sharing of such rules. Comprehensive analysis of 23 TFs, each with ChIP-Seq data in 4-12 cell-types, shows that by explicitly capturing the heterogeneity of binding rules, TRISECT accurately identifies in vivo TF occupancy (93%) substantially improving upon previous methods. Importantly, many of the binding rules derived from individual cell-types are shared across cell-types and reveal distinct yet functionally coherent putative target genes in different cell-types. Closer inspection of the predicted cell-type-specific interaction partners provides insights into context-specific functional landscape of a TF. Together, our novel ensemble-based approach reveals, for the first time, a widespread heterogeneity of binding rules, comprising interaction partners within a cell-type, many of which nevertheless transcend cell-types. Notably, the putative targets of shared binding rules in different cell-types, while distinct, exhibit significant functional coherence.

scholarly journals Cell-type Specific Expression Quantitative Trait Loci Associated with Alzheimer Disease in Blood and Brain Tissue

2020 ◽  
Author(s):  
Devanshi Patel ◽  
Xiaoling Zhang ◽  
John J. Farrell ◽  
Jaeyoon Chung ◽  
Thor D. Stein ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quantitative Trait ◽  
Expression Patterns ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Eqtl Analysis ◽  
Cell Type ◽  
Specific Expression ◽  
Cell Type Specific Expression ◽  
Cell Type Specific

ABSTRACTBecause regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell-types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5,257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1Mb of genes was evaluated using linear regression models for unrelated subjects and linear mixed models for related subjects. Cell type-specific eQTL (ct-eQTL) models included an interaction term for expression of “proxy” genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2,533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell-types is supported by the observation that a large portion of GWS ct-eQTLs map within 1Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type specific analysis.

scholarly journals miR-27 and miR-125 Distinctly Regulate Muscle-Enriched Transcription Factors in Cardiac and Skeletal Myocytes

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Estefania Lozano-Velasco ◽  
Jennifer Galiano-Torres ◽  
Alvaro Jodar-Garcia ◽  
Amelia E. Aranega ◽  
Diego Franco
Keyword(s):  
Transcription Factors ◽  
Cardiac Development ◽  
Protein Translation ◽  
Cell Type ◽  
Atrial Cardiomyocytes ◽  
Skeletal Myocytes ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific

MicroRNAs are noncoding RNAs of approximately 22–24 nucleotides which are capable of interacting with the 3′ untranslated region of coding RNAs (mRNAs), leading to mRNA degradation and/or protein translation blockage. In recent years, differential microRNA expression in distinct cardiac development and disease contexts has been widely reported, yet the role of individual microRNAs in these settings remains largely unknown. We provide herein evidence of the role of miR-27 and miR-125 regulating distinct muscle-enriched transcription factors. Overexpression of miR-27 leads to impair expression ofMstnandMyocdin HL1 atrial cardiomyocytes but not in Sol8 skeletal muscle myoblasts, while overexpression of miR-125 resulted in selective upregulation ofMef2din HL1 atrial cardiomyocytes and downregulation in Sol8 cells. Taken together our data demonstrate that a single microRNA, that is, miR-27 or miR-125, can selectively upregulate and downregulate discrete number of target mRNAs in a cell-type specific manner.

scholarly journals Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas

2001 ◽  
Vol 21 (6) ◽  
pp. 2144-2153 ◽  
Author(s):  
Nabeel Bardeesy ◽  
Boris C. Bastian ◽  
Aram Hezel ◽  
Dan Pinkel ◽  
Ronald A. DePinho ◽  
...  
Keyword(s):  
Tumor Cells ◽  
P53 Mutation ◽  
Comparative Genomic ◽  
Cell Type ◽  
Specific Expression ◽  
Rb Pathway ◽  
High Incidence ◽  
A Cell ◽  
Cell Type Specific

ABSTRACT The frequent loss of both INK4a and ARF in melanoma raises the question of which INK4a-ARF gene product functions to suppress melanoma genesis in vivo. Moreover, the high incidence of INK4a-ARF inactivation in transformed melanocytes, along with the lack of p53 mutation, implies a cell type-specific role for INK4a-ARF that may not be complemented by other lesions of the RB and p53 pathways. A mouse model of cutaneous melanoma has been generated previously through the combined effects of INK4a Δ2/3 deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RASV12G, Tyr-RAS). In this study, we made use of this Tyr-RAS allele to determine whether activated RAS can cooperate withp53 loss in melanoma genesis, whether such melanomas are biologically comparable to those arising inINK4a Δ2/3−/− mice, and whether tumor-associated mutations emerge in the p16INK4a-RB pathway in such melanomas. Here, we report that p53inactivation can cooperate with activated RAS to promote the development of cutaneous melanomas that are clinically indistinguishable from those arisen on theINK4a Δ2/3 null background. Genomewide analysis of RAS-induced p53 mutant melanomas by comparative genomic hybridization and candidate gene surveys revealed alterations of key components governing RB-regulated G1/S transition, including c-Myc, cyclin D1, cdc25a, and p21CIP1. Consistent with the profile of c-Myc dysregulation, the reintroduction of p16INK4a profoundly reduced the growth of Tyr-RASINK4a Δ2/3−/− tumor cells but had no effect on tumor cells derived from Tyr-RAS p53 −/−melanomas. Together, these data validate a role for p53inactivation in melanomagenesis and suggest that both the RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.

scholarly journals The complement of desmosomal plaque proteins in different cell types.

1985 ◽  
Vol 101 (4) ◽  
pp. 1442-1454 ◽  
Author(s):  
P Cowin ◽  
H P Kapprell ◽  
W W Franke
Keyword(s):  
Guinea Pig ◽  
Cell Types ◽  
Cardiac Cells ◽  
Myocardial Tissue ◽  
Cell Type ◽  
Wide Range ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific ◽  
Different Cell Types

Desmosomal plaque proteins have been identified in immunoblotting and immunolocalization experiments on a wide range of cell types from several species, using a panel of monoclonal murine antibodies to desmoplakins I and II and a guinea pig antiserum to desmosomal band 5 protein. Specifically, we have taken advantage of the fact that certain antibodies react with both desmoplakins I and II, whereas others react only with desmoplakin I, indicating that desmoplakin I contains unique regions not present on the closely related desmoplakin II. While some of these antibodies recognize epitopes conserved between chick and man, others display a narrow species specificity. The results show that proteins whose size, charge, and biochemical behavior are very similar to those of desmoplakin I and band 5 protein of cow snout epidermis are present in all desmosomes examined. These include examples of simple and pseudostratified epithelia and myocardial tissue, in addition to those of stratified epithelia. In contrast, in immunoblotting experiments, we have detected desmoplakin II only among cells of stratified and pseudostratified epithelial tissues. This suggests that the desmosomal plaque structure varies in its complement of polypeptides in a cell-type specific manner. We conclude that the obligatory desmosomal plaque proteins, desmoplakin I and band 5 protein, are expressed in a coordinate fashion but independently from other differentiation programs of expression such as those specific for either epithelial or cardiac cells.

scholarly journals Mechanisms Underlying Hox-Mediated Transcriptional Outcomes

2021 ◽  
Vol 9 ◽  
Author(s):  
Brittany Cain ◽  
Brian Gebelein
Keyword(s):  
Transcription Factors ◽  
Differentially Express ◽  
Target Genes ◽  
Cell Type ◽  
Cell Fates ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific ◽  
Anterior Posterior ◽  
Anterior Posterior Axis

Metazoans differentially express multiple Hox transcription factors to specify diverse cell fates along the developing anterior-posterior axis. Two challenges arise when trying to understand how the Hox transcription factors regulate the required target genes for morphogenesis: First, how does each Hox factor differ from one another to accurately activate and repress target genes required for the formation of distinct segment and regional identities? Second, how can a Hox factor that is broadly expressed in many tissues within a segment impact the development of specific organs by regulating target genes in a cell type-specific manner? In this review, we highlight how recent genomic, interactome, and cis-regulatory studies are providing new insights into answering these two questions. Collectively, these studies suggest that Hox factors may differentially modify the chromatin of gene targets as well as utilize numerous interactions with additional co-activators, co-repressors, and sequence-specific transcription factors to achieve accurate segment and cell type-specific transcriptional outcomes.

scholarly journals Cell type-specific biotin labeling in vivo resolves regional neuronal proteomic differences in mouse brain

2021 ◽  
Author(s):  
Sruti Rayaprolu ◽  
Sara Bitarafan ◽  
Ranjita Betarbet ◽  
Sydney N Sunna ◽  
Lihong Cheng ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Neurological Diseases ◽  
Neuronal Cell ◽  
Cell Types ◽  
Proteomic Profiling ◽  
Cell Type ◽  
Specific Expression ◽  
Cell Type Specific ◽  
The Brain

Isolation and proteomic profiling of brain cell types, particularly neurons, pose several technical challenges which limit our ability to resolve distinct cellular phenotypes in neurological diseases. Therefore, we generated a novel mouse line that enables cell type-specific expression of a biotin ligase, TurboID, via Cre-lox strategy for in vivo proximity-dependent biotinylation of proteins. Using adenoviral-based and transgenic approaches, we show striking protein biotinylation in neuronal cell bodies and axons throughout the mouse brain. We quantified more than 2,000 neuron-derived proteins following enrichment that mapped to numerous subcellular compartments. Synaptic, transmembrane transporters, ion channel subunits, and disease-relevant druggable targets were among the most significantly enriched proteins. Remarkably, we resolved brain region-specific proteomic profiles of Camk2a neurons with distinct functional molecular signatures and disease associations that may underlie regional neuronal vulnerability. Leveraging the neuronal specificity of this in vivo biotinylation strategy, we used an antibody-based approach to uncover regionally unique patterns of neuron-derived signaling phospho-proteins and cytokines, particularly in the cortex and cerebellum. Our work provides a proteomic framework to investigate cell type-specific mechanisms driving physiological and pathological states of the brain as well as complex tissues beyond the brain.

scholarly journals The role of SOX proteins in normal pituitary development

2008 ◽  
Vol 200 (3) ◽  
pp. 245-258 ◽  
Author(s):  
Kyriaki S Alatzoglou ◽  
Daniel Kelberman ◽  
Mehul T Dattani
Keyword(s):  
Transcription Factors ◽  
Expression Patterns ◽  
Cell Types ◽  
Transgenic Animal ◽  
Developmental Abnormalities ◽  
Pituitary Development ◽  
Organ Systems ◽  
Sox Proteins

Pituitary development is a complex process that depends on the co-ordinated spatial and temporal expression of transcription factors and signalling molecules that culminates in the formation of a complex organ that secretes six hormones from five different cell types. Given the fact that all distinct hormone producing cells arise from a common ectodermal primordium, the patterning, architecture and plasticity of the gland is impressive. Among the transcription factors involved in the early steps of pituitary organogenesis are SOX2 and SOX3, members of the SOX family that are emerging as key players in many developmental processes. Studies in vitro and in vivo in transgenic animal models have helped to elucidate their expression patterns and roles in the developing hypothalamo–pituitary region. It has been demonstrated that they may be involved in pituitary development either directly, through shaping of Rathke's pouch, or indirectly affecting signalling from the diencephalon. Their role has been further underlined by the pleiotropic effects of their mutations in humans that range from isolated hormone deficiencies to panhypopituitarism and developmental abnormalities affecting many organ systems. However, the exact mechanism of action of SOX proteins, their downstream targets and their interplay within the extensive network that regulates pituitary development is still the subject of a growing number of studies. The elucidation of their role is crucial for the understanding of a number of processes that range from developmental mechanisms to disease phenotypes and tumorigenesis.

scholarly journals Single-Cell Regulatory Network Inference and Clustering Identifies Cell-Type Specific Expression Pattern of Transcription Factors in Mouse Sciatic Nerve

2021 ◽  
Vol 15 ◽  
Author(s):  
Mingchao Li ◽  
Qing Min ◽  
Matthew C. Banton ◽  
Xinpeng Dun
Keyword(s):  
Transcription Factors ◽  
Sciatic Nerve ◽  
Single Cell ◽  
Cell Types ◽  
Cell Type ◽  
Specific Expression ◽  
Single Cell Rna Sequencing ◽  
Cell Type Specific Expression ◽  
Cell Type Specific ◽  
Different Cell Types

Advances in single-cell RNA sequencing technologies and bioinformatics methods allow for both the identification of cell types in a complex tissue and the large-scale gene expression profiling of various cell types in a mixture. In this report, we analyzed a single-cell RNA sequencing (scRNA-seq) dataset for the intact adult mouse sciatic nerve and examined cell-type specific transcription factor expression and activity during peripheral nerve homeostasis. In total, we identified 238 transcription factors expressed in nine different cell types of intact mouse sciatic nerve. Vascular smooth muscle cells have the lowest number of transcription factors expressed with 17 transcription factors identified. Myelinating Schwann cells (mSCs) have the highest number of transcription factors expressed, with 61 transcription factors identified. We created a cell-type specific expression map for the identified 238 transcription factors. Our results not only provide valuable information about the expression pattern of transcription factors in different cell types of adult peripheral nerves but also facilitate future studies to understand the function of key transcription factors in the peripheral nerve homeostasis and disease.

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