Four-dimensional chromosome reconstruction elucidates the spatiotemporal reorganization of the mammalian X chromosome

2021 ◽  
Vol 118 (42) ◽  
pp. e2107092118
Author(s):  
Anna Lappala ◽  
Chen-Yu Wang ◽  
Andrea Kriz ◽  
Hunter Michalk ◽  
Kevin Tan ◽  
...  
Keyword(s):  
X Chromosome ◽  
Large Scale ◽  
Three Dimensions ◽  
Rna Molecules ◽  
Chromosome Architecture ◽  
Inactive X Chromosome ◽  
Mixing Dynamics ◽  
Chromosome Reconstruction ◽  
Slow Mixing ◽  
3D Information

Chromosomes are segmented into domains and compartments, but how these structures are spatially related in three dimensions (3D) is unclear. Here, we developed tools that directly extract 3D information from Hi-C experiments and integrate the data across time. With our “4DHiC” method, we use X chromosome inactivation (XCI) as a model to examine the time evolution of 3D chromosome architecture during large-scale changes in gene expression. Our modeling resulted in several insights. Both A/B and S1/S2 compartments divide the X chromosome into hemisphere-like structures suggestive of a spatial phase-separation. During the XCI, the X chromosome transits through A/B, S1/S2, and megadomain structures by undergoing only partial mixing to assume new structures. Interestingly, when an active X chromosome (Xa) is reorganized into an inactive X chromosome (Xi), original underlying compartment structures are not fully eliminated within the Xi superstructure. Our study affirms slow mixing dynamics in the inner chromosome core and faster dynamics near the surface where escapees reside. Once established, the Xa and Xi resemble glassy polymers where mixing no longer occurs. Finally, Xist RNA molecules initially reside within the A compartment but transition to the interface between the A and B hemispheres and then spread between hemispheres via both surface and core to establish the Xi.

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 4D chromosome reconstruction elucidates the spatial reorganization of the mammalian X-chromosome

2021 ◽  
Author(s):  
Anna Lappala ◽  
Chen-Yu Wang ◽  
Andrea Kriz ◽  
Hunter Michalk ◽  
Kevin Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Principal Component ◽  
Reaction Diffusion ◽  
Chromosome Architecture ◽  
3D Space ◽  
Xist Rna ◽  
Spatial Reorganization ◽  
Chromosome Reconstruction ◽  
Scale Structures

AbstractChromosomes are segmented into domains and compartments; yet, how these structures are spatially related in 3D is unclear. Here, by directly integrating Hi-C capture experiments and 3D modeling, we use X-inactivation as a model to examine the time evolution of 3D chromosome architecture during substantial changes in gene expression. First, we show that gene expression A/B compartments are consistent with phase separation in 3D space. Second, we show that residuals of smaller scale structures persist through transitions, despite further large-scale reorganization into the final inactive configuration, comprising two “megadomains”. Interestingly, these previously hidden residual structures were not detectable in 2D Hi-C maps or principal component analyses. Third, time-dependent reaction-diffusion simulations reveal how Xist RNA particles diffuse across the 3D X-superstructure as it reorganizes. Our 4DHiC pipeline helps satisfy the growing demand for methodologies that produce 3D chromosome reconstructions directly from 2D datasets, which are consistent with the empirical data.

X-Chromosome Inactivation: A Crossroads Between Chromosome Architecture and Gene Regulation

2018 ◽  
Vol 52 (1) ◽  
pp. 535-566 ◽  
Author(s):  
Rafael Galupa ◽  
Edith Heard
Keyword(s):  
X Chromosome ◽  
Current Knowledge ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Female Development ◽  
Barr Body ◽  
Chromosome Conformation ◽  
X Chromosomes ◽  
Chromosome Architecture ◽  
Inactive X Chromosome

In somatic nuclei of female therian mammals, the two X chromosomes display very different chromatin states: One X is typically euchromatic and transcriptionally active, and the other is mostly silent and forms a cytologically detectable heterochromatic structure termed the Barr body. These differences, which arise during female development as a result of X-chromosome inactivation (XCI), have been the focus of research for many decades. Initial approaches to define the structure of the inactive X chromosome (Xi) and its relationship to gene expression mainly involved microscopy-based approaches. More recently, with the advent of genomic techniques such as chromosome conformation capture, molecular details of the structure and expression of the Xi have been revealed. Here, we review our current knowledge of the 3D organization of the mammalian X-chromosome chromatin and discuss its relationship with gene activity in light of the initiation, spreading, and maintenance of XCI, as well as escape from gene silencing.

scholarly journals Mouse Polycomb Proteins Bind Differentially to Methylated Histone H3 and RNA and Are Enriched in Facultative Heterochromatin

2006 ◽  
Vol 26 (7) ◽  
pp. 2560-2569 ◽  
Author(s):  
Emily Bernstein ◽  
Elizabeth M. Duncan ◽  
Osamu Masui ◽  
Jesus Gil ◽  
Edith Heard ◽  
...  
Keyword(s):  
X Chromosome ◽  
Histone H3 ◽  
Facultative Heterochromatin ◽  
Rna Molecules ◽  
Polycomb Proteins ◽  
Inactive X Chromosome ◽  
Polycomb Protein ◽  
Preferential Binding

ABSTRACT The chromodomain (CD) of the Drosophila Polycomb protein exhibits preferential binding affinity for histone H3 when trimethylated at lysine 27. Here we have investigated the five mouse Polycomb homologs known as Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8. Despite a high degree of conservation, the Cbx chromodomains display significant differences in binding preferences. Not all CDs bind preferentially to K27me3; rather, some display affinity towards both histone H3 trimethylated at K9 and H3K27me3, and one CD prefers K9me3. Cbx7, in particular, displays strong affinity for both H3K9me3 and H3K27me3 and is developmentally regulated in its association with chromatin. Cbx7 associates with facultative heterochromatin and, more specifically, is enriched on the inactive X chromosome. Finally, we find that, in vitro, the chromodomain of Cbx7 can bind RNA and that, in vivo, the interaction of Cbx7 with chromatin, and the inactive X chromosome in particular, depends partly on its association with RNA. We propose that the capacity of this mouse Polycomb homolog to associate with the inactive X chromosome, or any other region of chromatin, depends not only on its chromodomain but also on the combination of histone modifications and RNA molecules present at its target sites.

New Models of Content Creation and Scholarship at the Intersection of Library Spaces, Technologies, and Expertise

2018 ◽  
Author(s):  
Mike Nutt ◽  
Gregory Raschke
Keyword(s):  
Large Scale ◽  
Interactive Media ◽  
Scholarly Communication ◽  
Three Dimensions ◽  
Organizational Capabilities ◽  
High Definition ◽  
Content Creation ◽  
Full Life Cycle ◽  
Digital Scholarship ◽  
Digital Objects

Library spaces that blend collaboration areas, advanced technologies, and librarian expertise are creating new modes of scholarly communication. These spaces enable scholarship created within high-definition, large-scale visual collaborative environments. This emergent model of scholarly communication can be experienced within those specific contexts or through digital surrogates on the networked Web. From experiencing in three dimensions the sermons of John Donne in 1622 to interactive media interpretations of American wars, scholars are partnering with libraries to create immersive digital scholarship. Viewing the library as a research platform for these emergent forms of digital scholarship presents several opportunities and challenges. Opportunities include re-engaging faculty in the use of library space, integrating the full life-cycle of the research enterprise, and engaging broad communities in the changing nature of digitally-driven scholarship. Issues such as identifying and filtering collaborations, strategically managing staff resources, creating surrogates of immersive digital scholarship, and preserving this content for the future present an array of challenges for libraries that require coordination across organizations. From engaging and using high-technology spaces to documenting the data and digital objects created, this developing scholarly communication medium brings to bear the multifaceted skills and organizational capabilities of libraries.

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