scholarly journals Cohesin is required for long-range enhancer action

2021 ◽  
Author(s):  
Lauren Kane ◽  
Iain Williamson ◽  
Ilya M Flyamer ◽  
Yatendra Kumar ◽  
Robert E Hill ◽  
...  
Keyword(s):  
Target Gene ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
Mammalian Genome ◽  
Ctcf Binding ◽  
Chromatin Compaction ◽  
Topologically Associating Domains ◽  
Cognate Gene ◽  
Distal Regulatory Elements ◽  
Regulatory Landscapes

The mammalian genome is organised into topologically associating domains (TADs) that are formed through the process of cohesin-driven loop extrusion and whose extent is constrained at TAD boundaries by orientation-dependent CTCF binding. The large regulatory landscapes of developmental genes frequently correspond to TADs, leading to the hypothesis that TADs and/or loop extrusion are important for enhancers to act on their cognate gene. However, it has proven hard to interpret the consequences of experimental disruption of TADs or loop-extrusion on gene regulation, in part because of the difficulty in distinguishing direct from indirect effects on enhancer-driven gene expression. By coupling acute protein degradation with synthetic activation by targeted transcription factor recruitment in mouse embryonic stem cells, here we show that cohesin, but not CTCF, is required for activation of a target gene by distant distal regulatory elements. Cohesin is not required for activation directly at the promoter or activation from an enhancer located closer to the gene. Our findings support the hypothesis that chromatin compaction mediated by cohesin-mediated loop extrusion allows for genes to be activated by regulatory elements that are located many hundreds of kilobases away in the linear genome but suggests that cohesin is dispensable for more genomically close enhancers.

scholarly journals CDK-Mediator and FBXL19 prime developmental genes for activation by promoting atypical regulatory interactions

2020 ◽  
Vol 48 (6) ◽  
pp. 2942-2955 ◽  
Author(s):  
Angelika Feldmann ◽  
Emilia Dimitrova ◽  
Alexander Kenney ◽  
Anna Lastuvkova ◽  
Robert J Klose
Keyword(s):  
Cpg Island ◽  
Gene Activation ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
Gene Induction ◽  
Gene Promoters ◽  
Developmental Gene ◽  
Gene Regulatory Elements ◽  
Gene Regulatory ◽  
Distal Regulatory Elements

Abstract Appropriate developmental gene regulation relies on the capacity of gene promoters to integrate inputs from distal regulatory elements, yet how this is achieved remains poorly understood. In embryonic stem cells (ESCs), a subset of silent developmental gene promoters are primed for activation by FBXL19, a CpG island binding protein, through its capacity to recruit CDK-Mediator. How mechanistically these proteins function together to prime genes for activation during differentiation is unknown. Here we discover that in mouse ESCs FBXL19 and CDK-Mediator support long-range interactions between silent gene promoters that rely on FBXL19 for their induction during differentiation and gene regulatory elements. During gene induction, these distal regulatory elements behave in an atypical manner, in that the majority do not acquire histone H3 lysine 27 acetylation and no longer interact with their target gene promoter following gene activation. Despite these atypical features, we demonstrate by targeted deletions that these distal elements are required for appropriate gene induction during differentiation. Together these discoveries demonstrate that CpG-island associated gene promoters can prime genes for activation by communicating with atypical distal gene regulatory elements to achieve appropriate gene expression.

scholarly journals Topologically Associating Domains and Regulatory Landscapes in Development, Evolution and Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Juan J. Tena ◽  
José M. Santos-Pereira
Keyword(s):  
Gene Regulation ◽  
Evolutionary Conservation ◽  
Regulatory Elements ◽  
Regulatory Interactions ◽  
Pathological Conditions ◽  
Topologically Associating Domains ◽  
Recent Advances ◽  
Development And Differentiation ◽  
Regulatory Landscapes ◽  
Animal Genomes

Animal genomes are folded in topologically associating domains (TADs) that have been linked to the regulation of the genes they contain by constraining regulatory interactions between cis-regulatory elements and promoters. Therefore, TADs are proposed as structural scaffolds for the establishment of regulatory landscapes (RLs). In this review, we discuss recent advances in the connection between TADs and gene regulation, their relationship with gene RLs and their dynamics during development and differentiation. Moreover, we describe how restructuring TADs may lead to pathological conditions, which explains their high evolutionary conservation, but at the same time it provides a substrate for the emergence of evolutionary innovations that lay at the origin of vertebrates and other phylogenetic clades.

scholarly journals CTCF knockout in zebrafish induces alterations in regulatory landscapes and developmental gene expression

2020 ◽  
Author(s):  
Martin Franke ◽  
Elisa de la Calle-Mustienes ◽  
Ana Neto ◽  
Rafael Acemel ◽  
Juan Tena ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Long Range ◽  
Chromatin Structure ◽  
Ctcf Binding ◽  
Developmental Gene ◽  
Developmental Genes ◽  
Chromatin Interactions ◽  
Topologically Associating Domains ◽  
Regulatory Landscapes

Abstract CTCF is an 11-zinc-finger DNA-binding protein that acts as a transcriptional repressor and insulator as well as an architectural protein required for 3D genome folding. CTCF mediates long-range chromatin looping and is enriched at the boundaries of topologically associating domains, which are sub-megabase chromatin structures that are believed to facilitate enhancer-promoter interactions within regulatory landscapes. Although CTCF is essential for cycling cells and developing embryos, its in vitro removal has only modest effects over gene expression, challenging the concept that CTCF-mediated chromatin interactions and topologically associated domains are a fundamental requirement for gene regulation. Here we link the loss of chromatin structure and gene regulation in an in vivo model and during animal development. We generated a ctcf knockout mutant in zebrafish that allows us to monitor the effect of CTCF loss of function during embryo patterning and organogenesis. CTCF absence leads to loss of chromatin structure in zebrafish embryos and affects the expression of thousands of genes, including many developmental genes. In addition, chromatin accessibility, both at CTCF binding sites and cis-regulatory elements, is severely compromised in ctcf mutants. Probing chromatin interactions from developmental genes at high resolution, we further demonstrate that promoters fail to fully establish long-range contacts with their associated regulatory landscapes, leading to altered gene expression patterns and disruption of developmental programs. Our results demonstrate that CTCF and topologically associating domains are essential to regulate gene expression during embryonic development, providing the structural basis for the establishment of developmental gene regulatory landscapes.

scholarly journals CTCF knockout in zebrafish induces alterations in regulatory landscapes and developmental gene expression

2020 ◽  
Author(s):  
Martin Franke ◽  
Elisa De la Calle-Mustienes ◽  
Ana Neto ◽  
Rafael D. Acemel ◽  
Juan J. Tena ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Long Range ◽  
Chromatin Structure ◽  
Ctcf Binding ◽  
Developmental Gene ◽  
Developmental Genes ◽  
Chromatin Interactions ◽  
Topologically Associating Domains ◽  
Regulatory Landscapes

CTCF is an 11-zinc-finger DNA-binding protein that acts as a transcriptional repressor and insulator as well as an architectural protein required for 3D genome folding1–5. CTCF mediates long-range chromatin looping and is enriched at the boundaries of topologically associating domains, which are sub-megabase chromatin structures that are believed to facilitate enhancer-promoter interactions within regulatory landscapes 6–12. Although CTCF is essential for cycling cells and developing embryos13,14, its in vitro removal has only modest effects over gene expression5,15, challenging the concept that CTCF-mediated chromatin interactions and topologically associated domains are a fundamental requirement for gene regulation16–18. Here we link the loss of chromatin structure and gene regulation in an in vivo model and during animal development. We generated a ctcf knockout mutant in zebrafish that allows us to monitor the effect of CTCF loss of function during embryo patterning and organogenesis. CTCF absence leads to loss of chromatin structure in zebrafish embryos and affects the expression of thousands of genes, including many developmental genes. In addition, chromatin accessibility, both at CTCF binding sites and cis-regulatory elements, is severely compromised in ctcf mutants. Probing chromatin interactions from developmental genes at high resolution, we further demonstrate that promoters fail to fully establish long-range contacts with their associated regulatory landscapes, leading to altered gene expression patterns and disruption of developmental programs. Our results demonstrate that CTCF and topologically associating domains are essential to regulate gene expression during embryonic development, providing the structural basis for the establishment of developmental gene regulatory landscapes.

scholarly journals Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Paula Freire-Pritchett ◽  
Stefan Schoenfelder ◽  
Csilla Várnai ◽  
Steven W Wingett ◽  
Jonathan Cairns ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Target Gene ◽  
Target Genes ◽  
Embryonic Stem ◽  
Regulatory Elements ◽  
Dna Looping ◽  
Lineage Commitment ◽  
Gene Promoters ◽  
Putative Target ◽  
Target Promoters

Long-range cis-regulatory elements such as enhancers coordinate cell-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. Deciphering the interplay between the promoter connectivity and activity of cis-regulatory elements during lineage commitment is crucial for understanding developmental transcriptional control. Here, we use Promoter Capture Hi-C to generate a high-resolution atlas of chromosomal interactions involving ~22,000 gene promoters in human pluripotent and lineage-committed cells, identifying putative target genes for known and predicted enhancer elements. We reveal extensive dynamics of cis-regulatory contacts upon lineage commitment, including the acquisition and loss of promoter interactions. This spatial rewiring occurs preferentially with predicted changes in the activity of cis-regulatory elements and is associated with changes in target gene expression. Our results provide a global and integrated view of promoter interactome dynamics during lineage commitment of human pluripotent cells.

scholarly journals Wnt/β-catenin Pathway-Mediated PPARδ Expression during Embryonic Development Differentiation and Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 1854
Author(s):  
Tabinda Sidrat ◽  
Zia-Ur Rehman ◽  
Myeong-Don Joo ◽  
Kyeong-Lim Lee ◽  
Il-Keun Kong
Keyword(s):  
Embryonic Development ◽  
Transcriptional Activation ◽  
Target Gene ◽  
Developmental Stages ◽  
Embryonic Stem ◽  
Hereditary Diseases ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Stem Cell Regulation ◽  
Early Developmental

The Wnt/β-catenin signaling pathway plays a crucial role in early embryonic development. Wnt/β-catenin signaling is a major regulator of cell proliferation and keeps embryonic stem cells (ESCs) in the pluripotent state. Dysregulation of Wnt signaling in the early developmental stages causes several hereditary diseases that lead to embryonic abnormalities. Several other signaling molecules are directly or indirectly activated in response to Wnt/β-catenin stimulation. The crosstalk of these signaling factors either synergizes or opposes the transcriptional activation of β-catenin/Tcf4-mediated target gene expression. Recently, the crosstalk between the peroxisome proliferator-activated receptor delta (PPARδ), which belongs to the steroid superfamily, and Wnt/β-catenin signaling has been reported to take place during several aspects of embryonic development. However, numerous questions need to be answered regarding the function and regulation of PPARδ in coordination with the Wnt/β-catenin pathway. Here, we have summarized the functional activation of the PPARδ in co-ordination with the Wnt/β-catenin pathway during the regulation of several aspects of embryonic development, stem cell regulation and maintenance, as well as during the progression of several metabolic disorders.

scholarly journals Glucocorticoid receptor wields chromatin interactions to tune transcription for cytoskeleton stabilization in podocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hong Wang ◽  
Aiping Duan ◽  
Jing Zhang ◽  
Qi Wang ◽  
Yuexian Xing ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glucocorticoid Receptor ◽  
Protective Effect ◽  
Histone Modification ◽  
Regulatory Networks ◽  
Target Gene ◽  
Regulatory Elements ◽  
Chromatin Interactions ◽  
Super Enhancer

AbstractElucidating transcription mediated by the glucocorticoid receptor (GR) is crucial for understanding the role of glucocorticoids (GCs) in the treatment of diseases. Podocyte is a useful model for studying GR regulation because GCs are the primary medication for podocytopathy. In this study, we integrated data from transcriptome, transcription factor binding, histone modification, and genome topology. Our data reveals that the GR binds and activates selective regulatory elements in podocyte. The 3D interactome captured by HiChIP facilitates the identification of remote targets of GR. We found that GR in podocyte is enriched at transcriptional interaction hubs and super-enhancers. We further demonstrate that the target gene of the top GR-associated super-enhancer is indispensable to the effective functioning of GC in podocyte. Our findings provided insights into the mechanisms underlying the protective effect of GCs on podocyte, and demonstrate the importance of considering transcriptional interactions in order to fine-map regulatory networks of GR.

scholarly journals Large organized chromatin lysine domains help distinguish primitive from differentiated cell populations

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Seyed Ali Madani Tonekaboni ◽  
Benjamin Haibe-Kains ◽  
Mathieu Lupien
Keyword(s):  
Transposable Elements ◽  
Histone Modifications ◽  
Cell Types ◽  
Regulatory Elements ◽  
Cell Populations ◽  
Genomic Features ◽  
Differentiated Cells ◽  
Chromatin Interactions ◽  
Topologically Associating Domains ◽  
Highly Expressed Genes

AbstractThe human genome is partitioned into a collection of genomic features, inclusive of genes, transposable elements, lamina interacting regions, early replicating control elements and cis-regulatory elements, such as promoters, enhancers, and anchors of chromatin interactions. Uneven distribution of these features within chromosomes gives rise to clusters, such as topologically associating domains (TADs), lamina-associated domains, clusters of cis-regulatory elements or large organized chromatin lysine (K) domains (LOCKs). Here we show that LOCKs from diverse histone modifications discriminate primitive from differentiated cell types. Active LOCKs (H3K4me1, H3K4me3 and H3K27ac) cover a higher fraction of the genome in primitive compared to differentiated cell types while repressive LOCKs (H3K9me3, H3K27me3 and H3K36me3) do not. Active LOCKs in differentiated cells lie proximal to highly expressed genes while active LOCKs in primitive cells tend to be bivalent. Genes proximal to bivalent LOCKs are minimally expressed in primitive cells. Furthermore, bivalent LOCKs populate TAD boundaries and are preferentially bound by regulators of chromatin interactions, including CTCF, RAD21 and ZNF143. Together, our results argue that LOCKs discriminate primitive from differentiated cell populations.

Sign in / Sign up

Export Citation Format

Share Document