scholarly journals Gastrointestinal transcription factors drive lineage-specific developmental programs in organ specification and cancer

2019 ◽  
Vol 5 (12) ◽  
pp. eaax8898 ◽  
Author(s):  
Roshane Francis ◽  
Haiyang Guo ◽  
Catherine Streutker ◽  
Musaddeque Ahmed ◽  
Theodora Yung ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Epigenetic Regulation ◽  
Gastrointestinal Cancer ◽  
Chromatin Accessibility ◽  
Lineage Specification ◽  
Developmental Programs ◽  
Tissue Specific ◽  
Cancer Data ◽  
Gastrointestinal Tissue

Transcription factors (TFs) are spatially and temporally regulated during gut organ specification. Although accumulating evidence shows aberrant reactivation of developmental programs in cancer, little is known about how TFs drive lineage specification in development and cancer. We first defined gastrointestinal tissue–specific chromatin accessibility and gene expression during development, identifying the dynamic epigenetic regulation of SOX family of TFs. We revealed that Sox2 is not only essential for gastric specification, by maintaining chromatin accessibility at forestomach lineage loci, but also sufficient to promote forestomach/esophageal transformation upon Cdx2 deletion. By comparing our gastrointestinal lineage-specific transcriptome to human gastrointestinal cancer data, we found that stomach and intestinal lineage-specific programs are reactivated in Sox2high/Sox9high and Cdx2high cancers, respectively. By analyzing mice deleted for both Sox2 and Sox9, we revealed their potentially redundant roles in both gastric development and cancer, highlighting the importance of developmental lineage programs reactivated by gastrointestinal TFs in cancer.

Epigenetics of Cellular Memory: Insights from the Chromatin Accessibility Landscape of the Mitotic Genome

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4342-4342
Author(s):  
Chris C.S. Hsiung ◽  
Christapher Morrissey ◽  
Maheshi Udugama ◽  
Christopher Frank ◽  
Cheryl A. Keller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Transcription Factors ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Dnase I ◽  
Specific Gene ◽  
Tissue Specific ◽  
Dnase I Sensitivity ◽  
Mitotic Chromatin

Abstract Normal development requires the coordination of cell cycle progression and gene expression to produce physiologically appropriate cell numbers of various lineages. The concomitant dysregulation of these two cellular programs is central to many malignant and non-malignant hematologic diseases, yet researchers still lack clear, general principles of how intrinsic properties of cell division could influence transcriptional regulation. Mitosis is a unique phase of the cell cycle that dramatically disrupts transcription: chromosomes condense to form microscopically recognizable structures, the nucleus is disassembled, RNA synthesis ceases, and the transcription machinery and many transcription factors are evicted from mitotic chromatin. How cells “remember” tissue-specific transcriptional programs through mitotic divisions remains largely unknown. Some transcription factors, including the erythroid master regulator, GATA1, and certain chromatin features are known to remain associated with DNA during mitosis. These molecular entities have been proposed to serve as mitotic “bookmarks” -- molecules that store gene regulatory information at individual loci through mitosis. However, we have limited knowledge of the composition, mechanism and function of mitotic bookmarks. In this context, chromatin structure deserves special consideration, as chromosome condensation during mitosis could potentially hinder transcription factor binding. To obtain the first genome-wide view of chromatin accessibility during mitosis, we mapped the DNase I sensitivity of the interphase versus mitotic genome in two maturation stages in a murine erythroblast cell line, G1E. Despite microscopic condensation of chromosomes during mitosis, we found that DNase I sensitivity is extensively preserved throughout the mappable genome, indicating that mitotic chromatin is not as condensed as commonly presumed. Individual genes and cis-regulatory elements can maintain all, part of, or none of its interphase accessibility during mitosis, demonstrating that accessibility of mitotic chromatin is locally specified. Promoters generally maintain accessibility during mitosis; moreover, promoters with the highest degree of accessibility preservation in mitosis in G1E cells tend to also be accessible across many murine tissues in interphase. In contrast to promoters, we found that enhancer accessibility is preferentially lost during mitosis, raising the possibility that memory of enhancer regulation may be altered during mitosis. Since enhancers play crucial roles in specifying tissue-specific gene expression patterns, we propose that this phase of the cell cycle may be especially susceptible to resetting of transcriptional programs. This hypothesis is supported by our preliminary results that revealed aberrant RNA polymerase II re-engagement with the genome and transcript production in early G1. Thus, mitosis could be a source of gene expression heterogeneity, with potential implications for cell fate transitions in proliferative cells, such as during stem cell lineage commitment, experimental reprogramming, and tumorigenesis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comprehensive characterization of tissue-specific chromatin accessibility in L2 Caenorhabditis elegans nematodes

2020 ◽  
Author(s):  
Timothy J. Durham ◽  
Riza M. Daza ◽  
Louis Gevirtzman ◽  
Darren A. Cusanovich ◽  
William Stafford Noble ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Expression Patterns ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Gene Expression Patterns ◽  
Rna Seq ◽  
Cell Type ◽  
Tissue Specific ◽  
C Elegans

AbstractRecently developed single cell technologies allow researchers to characterize cell states at ever greater resolution and scale. C. elegans is a particularly tractable system for studying development, and recent single cell RNA-seq studies characterized the gene expression patterns for nearly every cell type in the embryo and at the second larval stage (L2). Gene expression patterns are useful for learning about gene function and give insight into the biochemical state of different cell types; however, in order to understand these cell types, we must also determine how these gene expression levels are regulated. We present the first single cell ATAC-seq study in C. elegans. We collected data in L2 larvae to match the available single cell RNA-seq data set, and we identify tissue-specific chromatin accessibility patterns that align well with existing data, including the L2 single cell RNA-seq results. Using a novel implementation of the latent Dirichlet allocation algorithm, we leverage the single-cell resolution of the sci-ATAC-seq data to identify accessible loci at the level of individual cell types, providing new maps of putative cell type-specific gene regulatory sites, with promise for better understanding of cellular differentiation and gene regulation in the worm.

FLT3ITD Target Enhancers Are Primed but Inaccessible in Fetal Hematopoietic Progenitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1228-1228
Author(s):  
Yanan Li ◽  
Riddhi M Patel ◽  
Emily Casey ◽  
Jeffrey A. Magee
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Target Gene ◽  
Target Genes ◽  
Conflicts Of Interest ◽  
Gene Activation ◽  
Chromatin Accessibility ◽  
Luciferase Reporter ◽  
Enhancer Activity ◽  
Target Gene Expression

The FLT3 Internal Tandem Duplication (FLT3ITD) is common somatic mutation in acute myeloid leukemia (AML). We have previously shown that FLT3ITD fails to induce changes in HSC self-renewal, myelopoiesis and leukemogenesis during fetal stages of life. FLT3ITD signal transduction pathways are hyperactivated in fetal progenitors, but FLT3ITD target genes are not. This suggests that postnatal-specific transcription factors may be required to help induce FLT3ITD target gene expression. Alternatively, repressive histone modifications may impose a barrier to FLT3ITD target gene activation in fetal HPCs that is relaxed during postnatal development. To resolve these possibilities, we used ATAC-seq, as well as H3K4me1, H3K27ac and H3K27me3 ChIP-seq, to identify cis-elements that putatively control FLT3ITD target gene expression in fetal and adult hematopoietic progenitor cells (HPCs). We identified many enhancer elements (ATAC-seq peaks with H3K4me1 and H3K27ac) that exhibited increased chromatin accessibility and activity in FLT3ITD adult HPCs relative to wild type adult HPCs. These elements were enriched near FLT3ITD target genes. HOMER analysis showed enrichment for STAT5, ETS, RUNX1 and IRF binding motifs within the FLT3ITD target enhancers, but motifs for temporally dynamic transcription factors were not identified. We cloned a subset of the enhancers and confirmed that they could synergize with their promoter to activate a luciferase reporter. For representative enhancers, STAT5 binding sites were required to activate the enhancer - as anticipated - and RUNX1 repressed enhancer activity. We tested whether accessibility or priming changed between fetal and adult stages of HPC development. FLT3ITD-dependent changes in chromatin accessibility were not observed in fetal HPCs, though the enhancers were primed early in development as evidenced by the presence of H3K4me1. Repressive H3K27me3 were not present at FLT3ITD target enhancers in either or adult HPCs. The data show that FLT3ITD target enhancers are demarcated early in hematopoietic development, long before they become responsive to FLT3ITD signaling. Repressive marks do not appear to create an epigenetic barrier to enhancer activation in the fetal stage. Instead, age-specific transcription factors are likely required to pioneer enhancer elements so that they can respond to STAT5 and other FLT3ITD effectors. Disclosures No relevant conflicts of interest to declare.

scholarly journals Complex Relationships between Chromatin Accessibility, Sequence Divergence, and Gene Expression in Arabidopsis thaliana

2017 ◽  
Vol 35 (4) ◽  
pp. 837-854 ◽  
Author(s):  
Cristina M Alexandre ◽  
James R Urton ◽  
Ken Jean-Baptiste ◽  
John Huddleston ◽  
Michael W Dorrity ◽  
...  
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Transcription Factors ◽  
Dna Sequences ◽  
Sequence Variation ◽  
Expression Patterns ◽  
Sequence Divergence ◽  
Chromatin Accessibility ◽  
Regulatory Dna ◽  
Regulatory Sites

AbstractVariation in regulatory DNA is thought to drive phenotypic variation, evolution, and disease. Prior studies of regulatory DNA and transcription factors across animal species highlighted a fundamental conundrum: Transcription factor binding domains and cognate binding sites are conserved, while regulatory DNA sequences are not. It remains unclear how conserved transcription factors and dynamic regulatory sites produce conserved expression patterns across species. Here, we explore regulatory DNA variation and its functional consequences within Arabidopsis thaliana, using chromatin accessibility to delineate regulatory DNA genome-wide. Unlike in previous cross-species comparisons, the positional homology of regulatory DNA is maintained among A. thaliana ecotypes and less nucleotide divergence has occurred. Of the ∼50,000 regulatory sites in A. thaliana, we found that 15% varied in accessibility among ecotypes. Some of these accessibility differences were associated with extensive, previously unannotated sequence variation, encompassing many deletions and ancient hypervariable alleles. Unexpectedly, for the majority of such regulatory sites, nearby gene expression was unaffected. Nevertheless, regulatory sites with high levels of sequence variation and differential chromatin accessibility were the most likely to be associated with differential gene expression. Finally, and most surprising, we found that the vast majority of differentially accessible sites show no underlying sequence variation. We argue that these surprising results highlight the necessity to consider higher-order regulatory context in evaluating regulatory variation and predicting its phenotypic consequences.

scholarly journals The Developmental Control of Osteoblast-Specific Gene Expression: Role of Specific Transcription Factors and the Extracellular Matrix Environment

1999 ◽  
Vol 10 (1) ◽  
pp. 40-57 ◽  
Author(s):  
R.T. Franceschi
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Dna Sequences ◽  
Developmental Process ◽  
Positional Information ◽  
Cleidocranial Dysplasia ◽  
Specific Gene ◽  
Tissue Specific ◽  
Specific Gene Expression ◽  
Specific Differentiation

Bone formation is a carefully controlled developmental process involving morphogen-mediated patterning signals that define areas of initial mesenchyme condensation followed by induction of cell-specific differentiation programs to produce chondrocytes and osteoblasts. Positional information is conveyed via gradients of molecules, such as Sonic Hedgehog that are released from cells within a particular morphogenic field together with region-specific patterns of hox gene expression. These, in turn, regulate the localized production of bone morphogenetic proteins and related molecules which initiate chondrocyte- and osteoblast-specific differentiation programs. Differentiation requires the initial commitment of mesenchymal stem cells to a given lineage, followed by induction of tissue-specific patterns of gene expression. Considerable information about the control of osteoblast-specific gene expression has come from analysis of the promoter regions of genes encoding proteins like osteocalcin that are selectively expressed in bone. Both general and tissue-specific transcription factors control this promoter. Osf2/Cbfal, the first osteoblast-specific transcription factor to be identified, is expressed early in the osteoblast lineage and interacts with specific DNA sequences in the osteocalcin promoter essential for its selective expression in osteoblasts. The OSF2/CBFA1 gene is necessary for the development of mineralized tissues, and its mutation causes the human disease, cleidocranial dysplasia. Committed osteoprogenitor cells already expressing Osf2/Cbfa1 must synthesize a collagenous ECM before they will differentiate. A ceII:ECM interaction mediated by integrin-type cell-surface receptors is essential for the induction of osteocalcin and other osteoblast-related proteins. This interaction stimulates the binding of Osf2/Cbfa 1 to the osteocalcin promoter through an as-yet-undefined mechanism.

scholarly journals FAK regulates IL-33 expression by controlling chromatin accessibility at c-Jun motifs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Billie G. C. Griffith ◽  
Rosanna Upstill-Goddard ◽  
Holly Brunton ◽  
Graeme R. Grimes ◽  
Andrew V. Biankin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Focal Adhesions ◽  
Gene Promoter ◽  
Chromatin Accessibility ◽  
Dependent Manner ◽  
Rna Seq ◽  
Interleukin 33 ◽  
Control Gene Expression ◽  
Differential Gene

AbstractFocal adhesion kinase (FAK) localizes to focal adhesions and is overexpressed in many cancers. FAK can also translocate to the nucleus, where it binds to, and regulates, several transcription factors, including MBD2, p53 and IL-33, to control gene expression by unknown mechanisms. We have used ATAC-seq to reveal that FAK controls chromatin accessibility at a subset of regulated genes. Integration of ATAC-seq and RNA-seq data showed that FAK-dependent chromatin accessibility is linked to differential gene expression, including of the FAK-regulated cytokine and transcriptional regulator interleukin-33 (Il33), which controls anti-tumor immunity. Analysis of the accessibility peaks on the Il33 gene promoter/enhancer regions revealed sequences for several transcription factors, including ETS and AP-1 motifs, and we show that c-Jun, a component of AP-1, regulates Il33 gene expression by binding to its enhancer in a FAK kinase-dependent manner. This work provides the first demonstration that FAK controls transcription via chromatin accessibility, identifying a novel mechanism by which nuclear FAK regulates biologically important gene expression.

scholarly journals Cis acting variation is common, can propagates across multiple regulatory layers, but is often buffered in developmental programs

2020 ◽  
Author(s):  
Swann Floc’hlay ◽  
Emily Wong ◽  
Bingqing Zhao ◽  
Rebecca R. Viales ◽  
Morgane Thomas-Chollier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Transcription Factors ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cis Acting ◽  
Dna Mutations ◽  
Allele Specific ◽  
Regulatory Dna ◽  
The Impact

AbstractPrecise patterns of gene expression are driven by interactions between transcription factors, regulatory DNA sequence, and chromatin. How DNA mutations affecting any one of these regulatory ‘layers’ is buffered or propagated to gene expression remains unclear. To address this, we quantified allele-specific changes in chromatin accessibility, histone modifications, and gene expression in F1 embryos generated from eight Drosophila crosses, at three embryonic stages, yielding a comprehensive dataset of 240 samples spanning multiple regulatory layers. Genetic variation in cis-regulatory elements is common, highly heritable, and surprisingly consistent in its effects across embryonic stages. Much of this variation does not propagate to gene expression. When it does, it acts through H3K4me3 or alternatively through chromatin accessibility and H3K27ac. The magnitude and evolutionary impact of mutations is influenced by a genes’ regulatory complexity (i.e. enhancer number), with transcription factors being most robust to cis-acting, and most influenced by trans-acting, variation. Overall, the impact of genetic variation on regulatory phenotypes appears context-dependent even within the constraints of embryogenesis.

scholarly journals FAK regulates IL-33 expression by controlling chromatin accessibility at c-Jun motifs

2020 ◽  
Author(s):  
Billie G. C. Griffith ◽  
Rosanna Upstill-Goddard ◽  
Holly Brunton ◽  
Graeme R. Grimes ◽  
Andrew V. Biankin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Focal Adhesions ◽  
Gene Promoter ◽  
Chromatin Accessibility ◽  
Dependent Manner ◽  
Rna Seq ◽  
Interleukin 33 ◽  
Control Gene Expression ◽  
Differential Gene

AbstractFocal adhesion kinase (FAK) localizes to focal adhesions and is overexpressed in many cancers. FAK can also translocate to the nucleus, where it binds to, and regulates, several transcription factors, including MBD2, p53 and IL-33, to control gene expression by unknown mechanisms. We have used ATAC-seq to reveal that FAK controls chromatin accessibility at a subset of regulated genes. Integration of ATAC-seq and RNA-seq data showed that FAK-dependent chromatin accessibility is linked to differential gene expression, including of the FAK-regulated cytokine and transcriptional regulator interleukin-33 (Il33), which controls anti-tumor immunity. Analysis of the accessibility peaks on the Il33 gene promoter/enhancer regions revealed sequences for several transcription factors, including ETS and AP-1 motifs, and we show that c-Jun, a component of AP-1, regulates Il33 gene expression by binding to its enhancer in a FAK kinase-dependent manner. This work provides the first demonstration that FAK controls transcription via chromatin accessibility, identifying a novel mechanism by which nuclear FAK regulates biologically important gene expression.

scholarly journals ATF3 drives senescence by reconstructing accessible chromatin profiles

2020 ◽  
Author(s):  
Chao Zhang ◽  
Xuebin Zhang ◽  
Yiting Guan ◽  
Xiaoke Huang ◽  
Lijun Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factors ◽  
Regulatory Mechanism ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Dynamic Landscape ◽  
Intergenic Regions ◽  
Senescence Program ◽  
Accessible Chromatin

AbstractChromatin architecture and gene expression profile undergo tremendous reestablishment during senescence. However, the regulatory mechanism between chromatin reconstruction and gene expression in senescence remain elusive. The chromatin accessibility is an excellent perspective to reveal the latent regulatory elements. Thus, we depicted the landscapes of chromatin accessibility and gene expression during HUVECs senescence. We found that chromatin accessibilities are re-distributed during senescence. The senescence related increased accessible regions (IARs) and the decreased accessible regions (DARs) are mainly distributed in distal intergenic regions. The DARs are correlated with the function declines caused by senescence, whereas the IARs are involved in the regulation for senescence program. Moreover, the heterochromatin contributes most of IARs in senescent cells. We identified that the AP-1 transcription factors, especially ATF3 is responsible for driving chromatin accessibility reconstruction in IARs. In particular, DNA methylation is negatively correlated with chromatin accessibility during senescence. AP-1 motifs with low DNA methylation may improve their binding affinity in IARs and further opens the chromatin nearby. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program. And we identified a cellular senescence regulator, AP-1, which promotes senescence through organizing the accessibility profile in IARs.

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