scholarly journals Deeply hidden genome organization directly mediated by SATB1

2021 ◽  
Author(s):  
Yoshinori Kohwi ◽  
Mari Grange ◽  
Hunter W Richards ◽  
Ya-Chen Liang ◽  
Cheng-Ming Chuong ◽  
...  
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Ctcf Binding ◽  
Specific Gene ◽  
Genome Architecture ◽  
Cell Type ◽  
Topologically Associated Domains ◽  
Chromatin Folding ◽  
Cell Type Specific ◽  
Cellular Phenotypes

Mammalian genomes are organized by multi-layered chromatin folding. Whether and how three-dimensional genome organization contributes to cell-type specific transcription remains unclear. Here we uncover genome architecture formed by specialized sequences, base-unpairing regions (BURs), bound to a nuclear architectural protein, SATB1. SATB1 regulates cell-type specific transcription that underlies changes in cellular phenotypes. We developed a modified ChIP-seq protocol that stringently purifies genomic DNA only with its directly-associated proteins and unmasked previously-hidden BURs as direct SATB1 targets genome-wide. These SATB1-bound BURs are mutually exclusive from CTCF binding sites, and SATB1 is dispensable for CTCF/cohesion-mediated topologically associated domains (TADs). Instead, BURs largely overlap with lamina associated domains (LADs), and the fraction of BURs tethered to the SATB1 protein network in the nuclear interior is cell type-dependent. Our results reveal TAD-independent chromatin folding mediated by BUR sequences, which serve as genome architecture landmarks targeted by SATB1, to regulate cell-type specific gene expression.

scholarly journals A super enhancer controls expression and chromatin architecture within the MHC class II locus

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Parimal Majumder ◽  
Joshua T. Lee ◽  
Andrew R. Rahmberg ◽  
Gaurav Kumar ◽  
Tian Mi ◽  
...  
Keyword(s):  
Mhc Class Ii ◽  
Three Dimensional ◽  
Class Ii ◽  
Ctcf Binding ◽  
Specific Gene ◽  
Mhc Ii ◽  
Chromatin Interactions ◽  
Super Enhancer ◽  
Cell Type Specific ◽  
Hla Dqa1

Super enhancers (SEs) play critical roles in cell type–specific gene regulation. The mechanisms by which such elements work are largely unknown. Two SEs termed DR/DQ-SE and XL9-SE are situated within the human MHC class II locus between the HLA-DRB1 and HLA-DQA1 genes and are highly enriched for disease-causing SNPs. To test the function of these elements, we used CRISPR/Cas9 to generate a series of mutants that deleted the SE. Deletion of DR/DQ-SE resulted in reduced expression of HLA-DRB1 and HLA-DQA1 genes. The SEs were found to interact with each other and the promoters of HLA-DRB1 and HLA-DQA1. DR/DQ-SE also interacted with neighboring CTCF binding sites. Importantly, deletion of DR/DQ-SE reduced the local chromatin interactions, implying that it functions as the organizer for the local three-dimensional architecture. These data provide direct mechanisms by which an MHC-II SE contributes to expression of the locus and suggest how variation in these SEs may contribute to human disease and altered immunity.

Differentiation: the selective potentiation of chromatin domains

Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4749-4755 ◽  
Author(s):  
J.A. Kramer ◽  
J.R. McCarrey ◽  
D. Djakiew ◽  
S.A. Krawetz
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Spermatogonial Stem Cell ◽  
Specific Gene ◽  
Cell Type ◽  
Chromatin Domains ◽  
Tissue Specific ◽  
Specific Gene Expression ◽  
Cell Type Specific ◽  
Cellular Phenotypes

Potentiation is requisite for the expression of our genome. It is the mechanism of opening chromatin domains to render genes accessible to tissue-specific and ubiquitous transacting-factors that enables transcription. The results presented in this study demonstrate that modulation of stage- and cell-type-specific gene expression during mammalian spermatogenesis involves selective potentiation of testis-expressed genes that reverses their repressive state when present in the spermatogonial stem cell. This directly contrasts hematopoiesis, which acts to selectively restrict lineage potential during differentiation from its permissive stem cell. These results are key to understanding how differentiative pathways are controlled and cellular phenotypes determined. A window to their modulation is presented.

scholarly journals Enhancer dependence of cell-type–specific gene expression increases with developmental age

2020 ◽  
Vol 117 (35) ◽  
pp. 21450-21458 ◽  
Author(s):  
Wenqing Cai ◽  
Jialiang Huang ◽  
Qian Zhu ◽  
Bin E. Li ◽  
Davide Seruggia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Developmental Stages ◽  
Three Dimensional ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Embryonic Cells ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Highly Correlated

How overall principles of cell-type–specific gene regulation (the “logic”) may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic, and three-dimensional (3D) genomic profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1, and Myb occupancy. EryP-/EryD-shared enhancers are highly correlated with red blood cell identity genes, whereas cell-type–specific regulation employs differentciselements in EryP and EryD cells. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes rely more on distal enhancers for regulation involving Myb-mediated enhancer activation. Gata1 HiChIP demonstrated an overall increased enhancer–promoter interactions at EryD-specific genes, whereas genome editing in selected loci confirmed distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer dependence of transcription, we observed a progressive reliance on cell-specific enhancers with increasing ontogenetic age among diverse tissues of mouse and human origin. Our findings highlight fundamental and conserved differences at distinct developmental stages, characterized by simpler promoter-centric regulation of cell-type–specific genes in embryonic cells and increased combinatorial enhancer-driven control in adult cells.

scholarly journals MyoD is a structure organizer of 3D genome architecture in muscle cells

2020 ◽  
Author(s):  
Qian Chen ◽  
Fengling Chen ◽  
Ruiting Wang ◽  
Minglei Shi ◽  
Antony K. Chen ◽  
...  
Keyword(s):  
Genome Organization ◽  
Three Dimensional ◽  
Muscle Cells ◽  
Cell Types ◽  
Linear Molecule ◽  
Basic Question ◽  
Genome Architecture ◽  
Cell Type ◽  
3D Genome ◽  
A Genome

AbstractThe genome is not a linear molecule of DNA randomly folded in the nucleus, but exists as an organized, three-dimensional (3D) dynamic architecture. Intriguingly, it is now clear that each cell type has a unique and characteristic 3D genome organization that functions in determining cell identity during development. A currently challenging basic question is how cell-type specific 3D genome structures are established during development. Herein, we analyzed 3D genome structures in primary myoblasts and myocytes from MyoD knockout (MKO) and wild type (WT) mice and discovered that MyoD, a pioneer transcription factor (TF), can function as a “genome organizer” that specifies the proper 3D genome architecture unique to muscle cell development. Importantly, we genetically demonstrate that H3K27ac is insufficient for establishing MyoD-induced chromatin loops in muscle cells. The establishment of MyoD’s “architectural role” should have profound impacts on advancing understanding of other pioneer transcription factors in orchestrating lineage specific 3D genome organization during development in a potentially very large number of cell types in diverse organisms.

scholarly journals The three-dimensional chromatin structure of the major human pancreatic cell types reveals lineage-specific regulatory architecture of T2D risk

2021 ◽  
Author(s):  
Su Chun ◽  
Long Gao ◽  
Catherine L May ◽  
James A Pippin ◽  
Keith Boehm ◽  
...  
Keyword(s):  
Single Cell ◽  
Target Genes ◽  
Genetic Diseases ◽  
Three Dimensional ◽  
Specific Gene ◽  
Cell Type ◽  
Pancreatic Cell ◽  
Regulatory Architecture ◽  
Cell Type Specific ◽  
Gene Regulatory

Three-dimensional (3D) chromatin organization maps help to dissect cell type-specific gene regulatory programs. Furthermore, 3D chromatin maps have contributed to elucidating the pathogenesis of complex genetic diseases by connecting distal regulatory regions and genetic risk variants to their respective target genes. To understand the cell type-specific regulatory architecture of diabetes risk, we generated transcriptomic and 3D epigenomic profiles of human pancreatic acinar, alpha, and beta cells using single-cell RNA-seq, single-cell ATAC-seq, and high-resolution Hi-C of sorted cells. Comparisons of these profiles revealed differential A/B (open/closed) chromatin compartmentalization, chromatin looping, and control of cell type-specific gene regulatory programs. We identified a total of 1,094 putative causal-variant-target-gene pairs at 129 type 2 diabetes GWAS signals using pancreatic 3D chromatin maps. We found that the connections between candidate causal variants and their putative target effector genes are cell-type stratified and emphasize previously underappreciated roles for alpha and acinar cells in diabetes pathogenesis

scholarly journals LncRNA:DNA triplex-forming sites are positioned at specific areas of genome organization and are predictors for Topologically Associated Domains

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Benjamin Soibam ◽  
Ayzhamal Zhamangaraeva
Keyword(s):  
Genome Organization ◽  
Chromatin Organization ◽  
Ctcf Binding ◽  
General Mechanism ◽  
Promoter Regions ◽  
Cellular Processes ◽  
A Genome ◽  
Topologically Associated Domains ◽  
Multiple Cell ◽  
Genomic Regions

Abstract Background Chromosomes are organized into units called topologically associated domains (TADs). TADs dictate regulatory landscapes and other DNA-dependent processes. Even though various factors that contribute to the specification of TADs have been proposed, the mechanism is not fully understood. Understanding the process for specification and maintenance of these units is essential in dissecting cellular processes and disease mechanisms. Results In this study, we report a genome-wide study that considers the idea of long noncoding RNAs (lncRNAs) mediating chromatin organization using lncRNA:DNA triplex-forming sites (TFSs). By analyzing the TFSs of expressed lncRNAs in multiple cell lines, we find that they are enriched in TADs, their boundaries, and loop anchors. However, they are evenly distributed across different regions of a TAD showing no preference for any specific portions within TADs. No relationship is observed between the locations of these TFSs and CTCF binding sites. However, TFSs are located not just in promoter regions but also in intronic, intergenic, and 3’UTR regions. We also show these triplex-forming sites can be used as predictors in machine learning models to discriminate TADs from other genomic regions. Finally, we compile a list of important “TAD-lncRNAs” which are top predictors for TADs identification. Conclusions Our observations advocate the idea that lncRNA:DNA TFSs are positioned at specific areas of the genome organization and are important predictors for TADs. LncRNA:DNA triplex formation most likely is a general mechanism of action exhibited by some lncRNAs, not just for direct gene regulation but also to mediate 3D chromatin organization.

scholarly journals Comprehensive analysis of single cell ATAC-seq data with SnapATAC

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rongxin Fang ◽  
Sebastian Preissl ◽  
Yang Li ◽  
Xiaomeng Hou ◽  
Jacinta Lucero ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Cell Analysis ◽  
Expression Patterns ◽  
Regulatory Elements ◽  
Cellular Heterogeneity ◽  
Specific Gene ◽  
Open Chromatin ◽  
Cell Type ◽  
Process Data ◽  
Cell Type Specific

AbstractIdentification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by sample heterogeneity. Single cell analysis of accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volume of data pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC dissects cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC is applied to 55,592 single-nucleus ATAC-seq profiles from the mouse secondary motor cortex. The analysis reveals ~370,000 candidate regulatory elements in 31 distinct cell populations in this brain region and inferred candidate cell-type specific transcriptional regulators.

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