Biology subjects

Abdennur, N.

Publications and source records attributed to Abdennur, N..

7 recordsLinked to original sources

bioRxiv2018

The genome-wide, multi-layered architecture of chromosome pairing in early Drosophila embryos

Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease. Here, we focused on trans interactions in Drosophila, where homologous chromosomes are paired in somatic cells from embryogenesis through adulthood. We first addressed the long-standing question of whether pairing extends genome-wide and, to this end, developed a haplotype-resolved Hi-C approach that uses a new strategy to minimize homolog misassignment and thus robustly distinguish trans-homolog from cis contacts. This approach revealed striking genome-wide pairing in Drosophila embryos. Moreover, we discovered pairing to be surprisingly structured, with trans-homolog domains and interaction peaks, many coinciding with the positions of analogous cis features. We also found a significant correlation between pairing and the chromatin accessibility mediated by the pioneer factor Zelda. Our findings reveal a complex, highly structured organization underlying homolog pairing, first discovered more than a century ago.\n\nOne Sentence SummaryA robust approach for haplotype-resolved Hi-C reveals highly-structured homolog pairing in early stage Drosophila embryos.

genetics↗

bioRxiv2018

Condensin II inactivation in interphase does not affect chromatin folding or gene expression

Condensin complexes have been proposed to play a prominent role in interphase chromatin organization and control of gene expression. Here, we report that the deletion of the central condensin II kleisin subunit Ncaph2 in differentiated mouse hepatocytes does not lead to significant changes in chromosome organization or in gene expression. Both observations challenge current views that implicate condensin in interphase chromosomal domain formation and in enhancer-promoter interactions. Instead, we suggest that the previously reported effects of condensin perturbation may result from their structural role during mitosis, which might indirectly impact the re-establishment of interphase chromosomal architecture after cell division.

genomics↗

bioRxiv2018

Emerging Evidence of Chromosome Folding by Loop Extrusion

Chromosome organization poses a remarkable physical problem with many biological consequences: how can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of loop extrusion with barrier elements, and review recent experimental studies that provide strong support for loop extrusion, focusing on perturbations to CTCF and cohesin assayed via Hi-C in interphase. Finally, we discuss a likely molecular mechanism of loop extrusion by SMC complexes.

genomics↗

bioRxiv2017

Chromatin Organization by an Interplay of Loop Extrusion and Compartmental Segregation

Mammalian chromatin is organized on length scales ranging from individual nucleosomes to chromosomal territories. At intermediate scales two dominant features emerge in interphase: (i) alternating regions (<5Mb) of active and inactive chromatin that spatially segregate into different compartments, and (ii) domains (<1Mb), i.e. regions that preferentially interact internally, which are also termed topologically associating domains (TADs) and are central to gene regulation. There is growing evidence that TADs are formed by active extrusion of chromatin loops by cohesin, whereas compartments are established by a phase separation process according to local chromatin states. Here we use polymer simulations to examine how the two processes, loop extrusion and compartmental segregation, work collectively and potentially interfere in shaping global chromosome organization. Our integrated model faithfully reproduces Hi-C data from previously puzzling experimental observations, where targeting of the TAD-forming machinery led to changes in compartmentalization. Specifically, depletion of chromatin-associated cohesin reduced TADs and revealed hidden, finer compartments, while increased processivity of cohesin led to stronger TADs and reduced compartmentalization, and depletion of the TAD boundary protein, CTCF, weakened TADs while leaving compartments unaffected. We reveal that these experimental perturbations are special cases of a general polymer phenomenon of active mixing by loop extrusion. This also predicts that interference with chromatin epigenetic states or nuclear volume would affect compartments but not TADs. Our results suggest that chromatin organization on the megabase scale emerges from competition of non-equilibrium active loop extrusion and epigenetically defined compartment structure.

biophysics↗

bioRxiv2017

HiGlass: Web-based Visual Comparison And Exploration Of Genome Interaction Maps

We present HiGlass, an open source visualization tool built on web technologies that provides a rich interface for rapid, multiplex, and multiscale navigation of 2D genomic maps alongside 1D genomic tracks, allowing users to combine various data types, synchronize multiple visualization modalities, and share fully customizable views with others. We demonstrate its utility in exploring different experimental conditions, comparing the results of analyses, and creating interactive snapshots to share with collaborators and the broader public. HiGlass is accessible online at http://higlass.io and is also available as a containerized application that can be run on any platform.

bioinformatics↗

bioRxiv2016

Targeted degradation of CTCF decouples local insulation of chromosome domains from higher-order genomic compartmentalization

The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and segmental organization into topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding, and CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Further, our data supports that CTCF mediates transcriptional insulator function through enhancer-blocking but not direct chromatin barrier activity. These results define the functions of CTCF in chromosome folding, and provide new fundamental insights into the rules governing mammalian genome organization.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC=\"FIGDIR/small/095802_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (49K):\norg.highwire.dtl.DTLVardef@79c6c5org.highwire.dtl.DTLVardef@e8e61forg.highwire.dtl.DTLVardef@5c2eedorg.highwire.dtl.DTLVardef@cf7f3_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2016

Two independent modes of chromosome organization are revealed by cohesin removal

The three-dimensional organization of chromosomes is tightly related to their biological function 1. Both imaging and chromosome conformation capture studies have revealed several layers of organization 2-4: segregation into active and inactive compartments at the megabase scale 5, and partitioning into domains (TADs) 6,7 and associated loops 8 at the sub-megabase scale. Yet, it remains unclear how these layers of genome organization form, interact with one another, and contribute to or result from genome activities. TADs seem to have critical roles in regulating gene expression by promoting or preventing interactions between promoters and distant cis-acting regulatory elements 9-14, and different architectural proteins, including cohesin, have been proposed to play central roles in their formation 15,16. However, experimental depletions of these proteins have resulted in marginal changes in chromosome organization 17-19. Here, we show that deletion of the cohesin-loading factor, Nipbl, leads to loss of chromosome-associated cohesin and results in dramatic genome reorganization. TADs and associated loops vanish globally, even in the absence of transcriptional changes. In contrast, segregation into compartments is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the 3D organization of the genome results from the independent action of two distinct mechanisms: 1) cohesin-independent segregation of the genome into fine-scale compartment regions, defined by the underlying chromatin state; and 2) cohes-dependent formation of TADs possibly by the recently proposed loop extrusion mechanism 20,21, enabling long-range and target-specific activity of promiscuous enhancers. The interplay between these mechanisms creates an architecture that is more complex than a simple hierarchy of layers and can be central to guiding normal development.

genomics↗