scholarly journals Long-range chromatin interactions on the inactive X and at Hox clusters are regulated by the non-canonical SMC protein Smchd1

2018 ◽  
Author(s):  
Natasha Jansz ◽  
Andrew Keniry ◽  
Marie Trussart ◽  
Heidi Bildsoe ◽  
Tamara Beck ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Long Range ◽  
X Chromosome ◽  
Chromatin Structure ◽  
Short Range ◽  
Higher Order ◽  
Chromatin Interactions ◽  
Inactive X Chromosome ◽  
Hox Clusters

AbstractThe regulation of higher order chromatin structure is complex and dynamic; however we do not yet understand the full suite of mechanisms governing architecture. Here we reveal the non-canonical SMC protein Smchd1 as a novel regulator of long-range chromatin interactions, and add it to the canon of epigenetic proteins required for Hox gene regulation. The effect of losing Smchd1-dependent chromatin interactions has varying outcomes dependent on chromatin context. At autosomal targets transcriptionally sensitive to Smchd1 deletion, we find increased short-range interactions and ectopic enhancer activation. By contrast, the inactive X chromosome is transcriptionally refractive to Smchd1 ablation, despite chromosome-wide increases in short-range interactions. There we observe spreading of H3K27me3 domains into regions not normally decorated by this mark. Together these data suggest Smchd1 has the capacity to insulate the chromatin, thereby limiting access to other chromatin modifying proteins.

Smchd1 regulates long-range chromatin interactions on the inactive X chromosome and at Hox clusters

2018 ◽  
Vol 25 (9) ◽  
pp. 766-777 ◽  
Author(s):  
Natasha Jansz ◽  
Andrew Keniry ◽  
Marie Trussart ◽  
Heidi Bildsoe ◽  
Tamara Beck ◽  
...  
Keyword(s):  
Long Range ◽  
X Chromosome ◽  
Chromatin Interactions ◽  
Inactive X Chromosome ◽  
Hox Clusters

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 Role of ATRX in chromatin structure and function: implications for chromosome instability and human disease

Reproduction ◽  
2011 ◽  
Vol 142 (2) ◽  
pp. 221-234 ◽  
Author(s):  
Rabindranath De La Fuente ◽  
Claudia Baumann ◽  
Maria M Viveiros
Keyword(s):  
Cancer Progression ◽  
X Chromosome ◽  
Chromatin Structure ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Chromosome Instability ◽  
Functional Differentiation ◽  
Diagnostic Tools ◽  
Control Of Gene Expression ◽  
Inactive X Chromosome

Functional differentiation of chromatin structure is essential for the control of gene expression, nuclear architecture, and chromosome stability. Compelling evidence indicates that alterations in chromatin remodeling proteins play an important role in the pathogenesis of human disease. Among these, α-thalassemia mental retardation X-linked protein (ATRX) has recently emerged as a critical factor involved in heterochromatin formation at mammalian centromeres and telomeres as well as facultative heterochromatin on the murine inactive X chromosome. Mutations in human ATRX result in an X-linked neurodevelopmental condition with various degrees of gonadal dysgenesis (ATRX syndrome). Patients with ATRX syndrome may exhibit skewed X chromosome inactivation (XCI) patterns, and ATRX-deficient mice exhibit abnormal imprinted XCI in the trophoblast cell line. Non-random or skewed XCI can potentially affect both the onset and severity of X-linked disease. Notably, failure to establish epigenetic modifications associated with the inactive X chromosome (Xi) results in several conditions that exhibit genomic and chromosome instability such as fragile X syndrome as well as cancer development. Insight into the molecular mechanisms of ATRX function and its interacting partners in different tissues will no doubt contribute to our understanding of the pathogenesis of ATRX syndrome as well as the epigenetic origins of aneuploidy. In turn, this knowledge will be essential for the identification of novel drug targets and diagnostic tools for cancer progression as well as the therapeutic management of global epigenetic changes commonly associated with malignant neoplastic transformation.

scholarly journals Orientation-dependent Dxz4 contacts shape the 3D structure of the inactive X chromosome

2017 ◽  
Author(s):  
G. Bonora ◽  
X. Deng ◽  
H. Fang ◽  
V. Ramani ◽  
R. Qui ◽  
...  
Keyword(s):  
Long Range ◽  
X Chromosome ◽  
3D Structure ◽  
Chromatin Accessibility ◽  
Ctcf Binding ◽  
Partial Restoration ◽  
Multiple Loci ◽  
Inactive X Chromosome ◽  
Repeat Locus ◽  
Contact Distribution

AbstractThe mammalian inactive X chromosome (Xi) condenses into a bipartite structure with two superdomains of frequent long-range contacts separated by a boundary or hinge region. Using in situ DNase Hi-C in mouse cells with deletions or inversions within the hinge we show that the conserved repeat locus Dxz4 alone is sufficient to maintain the bipartite structure and that Dxz4 orientation controls the distribution of long-range contacts on the Xi. Frequent long-range contacts between Dxz4 and the telomeric superdomain are either lost after its deletion or shifted to the centromeric superdomain after its inversion. This massive reversal in contact distribution is consistent with the reversal of CTCF motif orientation at Dxz4. De-condensation of the Xi after Dxz4 deletion is associated with partial restoration of TADs normally attenuated on the Xi. There is also an increase in chromatin accessibility and CTCF binding on the Xi after Dxz4 deletion or inversion, but few changes in gene expression, in accordance with multiple epigenetic mechanisms ensuring X silencing. We propose that Dxz4 represents a structural platform for frequent long-range contacts with multiple loci in a direction dictated by the orientation of a bank of CTCF motifs at Dxz4, which may work as a ratchet to form the distinctive bipartite structure of the condensed Xi.

ATRX in chromatin assembly and genome architecture during development and disease

2011 ◽  
Vol 89 (5) ◽  
pp. 435-444 ◽  
Author(s):  
Nathalie G. Bérubé
Keyword(s):  
Gene Regulation ◽  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Higher Order ◽  
Chromatin Assembly ◽  
Genome Architecture ◽  
Chromatin Conformation ◽  
Mammalian Development ◽  
Mitosis And Meiosis

The regulation of genome architecture is essential for a variety of fundamental cellular phenomena that underlie the complex orchestration of mammalian development. The ATP-dependent chromatin remodeling protein ATRX is emerging as a key regulatory component of nucleosomal dynamics and higher order chromatin conformation. Here we provide an overview of the role of ATRX at chromatin and during development, and discuss recent studies exposing a repertoire of ATRX functions at heterochromatin, in gene regulation, and during mitosis and meiosis. Exciting new progress on several fronts suggest that ATRX operates in histone variant deposition and in the modulation of higher order chromatin structure. Not surprisingly, dysfunction or absence of ATRX protein has devastating consequences on embryonic development and leads to human disease.

scholarly journals The non-canonical SMC protein SmcHD1 antagonises TAD formation on the inactive X chromosome

2018 ◽  
Author(s):  
Michal R Gdula ◽  
Tatyana B Nesterova ◽  
Greta Pintacuda ◽  
Jonathan Godwin ◽  
Ye Zhan ◽  
...  
Keyword(s):  
X Chromosome ◽  
Gene Activation ◽  
Higher Order ◽  
Partial Restoration ◽  
Chromosome Architecture ◽  
Inactive X Chromosome ◽  
Key Factor ◽  
Topologically Associated Domains ◽  
Unique Chromosome ◽  
Cpg Hypermethylation

AbstractThe inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), and formation of two mega-domains. In this study we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 null cells revealed the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred in an acute SmcHD1 knockout model, but in this case, independent of Xi gene de-repression. We conclude that SmcHD1 is a key factor in antagonising TAD formation on Xi.

scholarly journals Compartmap enables inference of higher-order chromatin structure in individual cells from scRNA-seq and scATAC-seq

2021 ◽  
Author(s):  
Benjamin K Johnson ◽  
Jean-Philippe Fortin ◽  
Kasper D. Hansen ◽  
Hui Shen ◽  
Timothy J. Triche
Keyword(s):  
Gene Regulation ◽  
Single Cell ◽  
Cell Lines ◽  
Chromatin Structure ◽  
Single Cells ◽  
Higher Order ◽  
Chromatin Domains ◽  
Structural Alterations ◽  
Chromatin Architecture ◽  
Single Cell Profiling

Single-cell profiling of chromatin structure remains a challenge due to cost, throughput, and resolution. We introduce compartmap to reconstruct higher-order chromatin domains in individual cells from transcriptomic (RNAseq) and epigenomic (ATACseq) assays. In cell lines and primary human samples, compartmap infers higher-order chromatin structure comparable to specialized chromatin capture methods, and identifies clinically relevant structural alterations in single cells. This provides a common lens to integrate transcriptional and epigenomic results, linking higher-order chromatin architecture to gene regulation and to clinically relevant phenotypes in individual cells.

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