Diverse silent chromatin states modulate genome compartmentalization and loop extrusion barriers

Abstract

The relationships between chromosomal compartmentalization, chromatin state and function are poorly understood. Here by profiling long-range contact frequencies in HCT116 colon cancer cells, we distinguish three silent chromatin states, comprising two types of heterochromatin and a state enriched for H3K9me2 and H2A.Z that exhibits neutral three-dimensional interaction preferences and which, to our knowledge, has not previously been characterized. We find that heterochromatin marked by H3K9me3, HP1α and HP1β correlates with strong compartmentalization. We demonstrate that disruption of DNA methyltransferase activity greatly remodels genome compartmentalization whereby domains lose H3K9me3-HP1α/β binding and acquire the neutrally interacting state while retaining late replication timing. Furthermore, we show that H3K9me3-HP1α/β heterochromatin is permissive to loop extrusion by cohesin but refractory to CTCF binding. Together, our work reveals a dynamic structural and organizational diversity of the silent portion of the genome and establishes connections between the regulation of chromatin state and chromosome organization, including an interplay between DNA methylation, compartmentalization and loop extrusion.

Unique territorial and sub-chromosomal organization revealed in the holocentric mothBombyx mori

“…To further characterize the three clusters, we profiled silent (H3K27me3, H3K9me3) and active (H3K36me3, H3K4me3) histone marks by ChIP-seq in the same PD-D2 embryonic stage of B. mori . We also included H2A.Z, as it has been involved in specifying a type of inactive chromatin state in colon cancer cells 24 , and H4K20me1, a mark that has been associated with a variety of processes including transcriptional regulation, chromosome replication and segregation, the DNA damage response as well as chromosome compaction 40,41 . One of the clusters is particularly enriched for active chromatin marks.…”

“…Compartment I domains show an overall homogeneous contact pattern across the chromosome with either conventional A or B compartments, while S segregates away from both. A recently described that B0 compartment identified in a colon cancer cell line also shows a neutral contact profile 24 . However, B0, as well as other compartment types, tend to interact with homotypic regions.…”

“…The function of S remains an intriguing question. It might be that the isolated genomic environment of these domains ensures the precise transcriptional regulation of the few genes present in compartment S. The fact that S-located genes are functionally enriched in transcription-related processes might suggest that S represents a developmental transition state to either A or B, as hypothesized for compartments I and B0 24,57,58 . Such a model is supported by the observation that these S domains are variable among different developmental stages.…”

“…Unlike most eukaryotes that have a locally restricted centromeric region, holocentric organisms have centromeric regions distributed along the entire length of chromosomes. Analyses of the spatial organization of holocentric chromosomes could lead to new organizational principles of the genome and help to deduce the role of centromeres in chromatin organization 23,24 . Nevertheless, 3D genome organization of holocentric organisms remains poorly understood.…”

A sub-set of guanine- and cytosine-rich genes are actively transcribed at the nuclear Lamin B1 region

“…To date, the presence of heterochromatic genes at the nuclear periphery (NP) was identified based on data generated from histone signatures, Hi-C, and Dam_ID methods [24][25][26][27] . To our knowledge, detailed approaches specifically using transcriptional profiling of the LB1 associated genes based on RNA polymerase II (RNA Pol II) activity has not yet been investigated in detail genome-wide.…”