High-Affinity Sites Form an Interaction Network to Facilitate Spreading of the MSL Complex across the X Chromosome in Drosophila

Ramírez, Fidel; Lingg, Thomas; Toscano, Sarah; Lam, Kin Chung; Georgiev, Plamen; Chung, Ho‐Ryun; Lajoie, Bryan R.; Wit, Elzo de; Ye, Zhan; Laat, Wouter de; Dekker, Job; Manke, Thomas; Akhtar, Asifa

doi:10.1016/j.molcel.2015.08.024

Cited by 73 publications

(135 citation statements)

References 51 publications

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“…In summary, we found that the overall architecture of the X chromosome is similar in male and female embryos, and similar to cell lines of male and female genotype, in line with previous observations [18]. In addition, we observed that slight differences in the three-dimensional contacts of X-chromosomal fragments (i.e., increased PC1 in the active compartment) correlate with higher H4K16ac levels in male compared to female cells.…”

Section: Resultssupporting

confidence: 90%

Chromosome topology guides the Drosophila Dosage Compensation Complex for target gene activation

et al. 2017

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X chromosome dosage compensation in requires chromosome-wide coordination of gene activation. The male-specific lethal dosage compensation complex (DCC) identifies and binds to X-chromosomal high-affinity sites (HAS) from which it boosts transcription. A sub-class of HAS, PionX sites, represent first contacts on the X. Here, we explored the chromosomal interactions of representative PionX sites by high-resolution 4C and determined the global chromosome conformation by Hi-C in sex-sorted embryos. Male and female X chromosomes display similar nuclear architecture, concordant with clustered, constitutively active genes. PionX sites, like HAS, are evenly distributed in the active compartment and engage in short- and long-range interactions beyond compartment boundaries. Long-range, inter-domain interactions between DCC binding sites are stronger in males, suggesting that the complex refines chromatin organization. By induction of DCC in female cells, we monitored the extent of activation surrounding PionX sites. This revealed a remarkable range of DCC action not only in linear proximity, but also at megabase distance if close in space, suggesting that DCC profits from pre-existing chromosome folding to activate genes.

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Section: Resultssupporting

confidence: 90%

Chromosome topology guides the Drosophila Dosage Compensation Complex for target gene activation

et al. 2017

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“…S17), in agreement with recently published observations (Ramírez et al 2015). Thus, it seems that hyperacetylation of male X Chromosomes due to dosage compensation (Akhtar and Becker 2000;Kind et al 2008) does not generate new TAD boundaries.…”

Section: Discussionsupporting

confidence: 91%

Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains

et al. 2015

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Recent advances enabled by the Hi-C technique have unraveled many principles of chromosomal folding that were subsequently linked to disease and gene regulation. In particular, Hi-C revealed that chromosomes of animals are organized into topologically associating domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression. Mechanisms that underlie partitioning of the genome into TADs remain poorly understood. To explore principles of TAD folding in Drosophila melanogaster, we performed Hi-C and poly(A) + RNA-seq in four cell lines of various origins (S2, Kc167, DmBG3-c2, and OSC). Contrary to previous studies, we find that regions between TADs (i.e., the inter-TADs and TAD boundaries) in Drosophila are only weakly enriched with the insulator protein dCTCF, while another insulator protein Su(Hw) is preferentially present within TADs. However, Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. Accordingly, we find that binding of insulator proteins dCTCF and Su(Hw) predicts TAD boundaries much worse than active chromatin marks do. Interestingly, inter-TADs correspond to decompacted inter-bands of polytene chromosomes, whereas TADs mostly correspond to densely packed bands. Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin. We propose the mechanism of TAD self-assembly based on the ability of nucleosomes from inactive chromatin to aggregate, and lack of this ability in acetylated nucleosomal arrays. Finally, we test this hypothesis by polymer simulations and find that TAD partitioning may be explained by different modes of inter-nucleosomal interactions for active and inactive chromatin.

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“…Second, the complex must spread to epigenetically marked active transcription units to disseminate the activating H4 acetylation . We and others suggested that this dissemination may involve dynamic interactions between chromosomal regions of primary binding and target genes in the active nuclear compartment . Our current study reveals that the DCC assembles at HAS already at the earliest developmental window we could interrogate by ChIP, but this binding does not immediately lead to maximal H4K16 acetylation.…”

Section: Resultsmentioning

confidence: 55%

“…These regions are highly enriched on the X ( Fig EV2B) and often contain a DNA sequence motif very similar to the known MRE motif ( Fig EV2C). Conceivably, many of these sites represent HAS that are known to often reside in introns [8,15]. Second, we observed 202 isolated MSL2 DNA binding events that are not associated with neighboring chromatin interactions (Figs 2A, and 3A and B).…”

Section: Chromatin Binding Of Msl2 Precedes Complete Dosage Compensationmentioning

confidence: 74%

Progressive dosage compensation during Drosophila embryogenesis is reflected by gene arrangement

Prayitno¹,

Schauer²,

Regnard³

et al. 2019

EMBO Reports

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In Drosophila melanogaster males, X‐chromosome monosomy is compensated by chromosome‐wide transcription activation. We found that complete dosage compensation during embryogenesis takes surprisingly long and is incomplete even after 10 h of development. Although the activating dosage compensation complex (DCC) associates with the X‐chromosome and MOF acetylates histone H4 early, many genes are not compensated. Acetylation levels on gene bodies continue to increase for several hours after gastrulation in parallel with progressive compensation. Constitutive genes are compensated earlier than developmental genes. Remarkably, later compensation correlates with longer distances to DCC binding sites. This time–space relationship suggests that DCC action on target genes requires maturation of the active chromosome compartment.

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High-Affinity Sites Form an Interaction Network to Facilitate Spreading of the MSL Complex across the X Chromosome in Drosophila

Cited by 73 publications

References 51 publications

Chromosome topology guides the Drosophila Dosage Compensation Complex for target gene activation

Chromosome topology guides the Drosophila Dosage Compensation Complex for target gene activation

Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains

Progressive dosage compensation during Drosophila embryogenesis is reflected by gene arrangement

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