PRC2-Associated Chromatin Contacts in the Developing Limb Reveal a Possible Mechanism for the Atypical Role of PRC2 in HoxA Gene Expression

Gentile, Claudia; Berlivet, Soizik; Mayran, Alexandre; Paquette, Denis; Guerard-Millet, Fanny; Bajon, Emmanuel; Dostie, Josée; Kmita, Marie

doi:10.1016/j.devcel.2019.05.021

Cited by 34 publications

(40 citation statements)

References 65 publications

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“…The colinear expression of Hox genes during limb formation provides a well-studied example of complex spatial and temporal inputs. At both the HoxD and HoxA loci, appropriate expression requires unique topological arrangements of the gene clusters and their respective long-range enhancers (Andrey et al, 2013;Berlivet et al, 2013;Gentile et al, 2019). At the HoxD locus, the TADs flanking the gene cluster match the dimensions of the regulatory regions with the 3′ landscape directing proximal limb expression and the 5′ landscape directing distal limb expression.…”

Section: Emergent Coherencementioning

confidence: 99%

The regulatory landscapes of developmental genes

Bolt

Duboule

2020

Development

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Regulatory landscapes have been defined in vertebrates as large DNA segments containing diverse enhancer sequences that produce coherent gene transcription. These genomic platforms integrate multiple cellular signals and hence can trigger pleiotropic expression of developmental genes. Identifying and evaluating how these chromatin regions operate may be difficult as the underlying regulatory mechanisms can be as unique as the genes they control. In this brief article and accompanying poster, we discuss some of the ways in which regulatory landscapes operate, illustrating these mechanisms using genes important for vertebrate development as examples. We also highlight some of the techniques available to researchers for analysing regulatory landscapes.

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Section: Emergent Coherencementioning

confidence: 99%

The regulatory landscapes of developmental genes

Bolt

Duboule

2020

Development

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“…This suggests that the interaction itself may not be altering the epigenetic state at the HOXA cluster, but rather play a role in establishing a scaffold in 3D nuclear space that promotes HOXA gene expression. This idea has also been echoed by several recent studies with the evidence that Polycomb target loci can act as permissive 3D genomic structure to allow the active transcription of Homeobox transcriptional factors 7,21 . It is well-established that transcriptionally active regions of the genome are enriched at the nuclear center while silent regions remain at the nuclear periphery 22 .…”

Section: Main Textmentioning

confidence: 93%

“…Overexpression of these HOXA genes is found in several acute myeloid leukemias (AML), where the genes are often directly targeted by chimeric proteins such as MLLfusions and NUP98-fusion 4,5 . Recent studies in mouse limb development have identified several enhancers interacting with the HOXA locus, contributing to their gene regulation during development 6,7 . As of yet, little is known about the role of 3D chromatin organization during hematopoiesis and whether distant enhancers are involved in the regulation of the HOXA genes in both normal and diseased states.…”

Section: Main Textmentioning

confidence: 99%

Three-dimensional regulation ofHOXAcluster genes by acis-element in hematopoietic stem cell and leukemia

Gore

Himadewi

et al. 2020

Preprint

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Proper gene regulation is crucial for cellular differentiation, and dysregulation of key genes can lead to diseased states such as cancer. The HOX transcription factors play such a role during hematopoiesis, and aberrant expression of certain HOXA genes is found in certain acute myeloid leukemias (AMLs). While studies have shown that these genes are targeted by a variety of mutant proteins including mutant NPM1, MLL fusions, and NUP98 fusions, little is known about how long-range 3D chromatin interactions regulate the HOXA genes in normal hematopoiesis and leukemia. Here, we report the interaction between the HOXA cluster with a ~1.3 Mb upstream DNA methylation Canyon termed "Geneless Canyon" (GLC) in human CD34+/CD38-hematopoietic stem cells (HSCs) and AML cell lines. We show that CRISPR-Cas9 mediated deletion of the whole GLC region reduces the expression of the distal HOXA genes and compromises HSC and leukemia cells self-renewal. This long-range chromatin interaction brings the HOXA cluster in contact with the nuclear pore complex (NPC) at the nuclear periphery, which promotes HOXA gene expression and maintains HSC and leukemia cell self-renewal. These findings reveal how long-range 3D chromatin organization regulates key transcription factor genes in both normal and diseased hematopoietic cells.

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“…Furthermore, the function of PRC2 in limb development is not restricted to gene silencing, as exemplified with the role of Eed in favoring enhancer-promoter contacts required for HoxA gene expression [8]. Together these findings highlight the increasing complexity behind the functional roles of the Polycomb repressive complexes in gene regulation.…”

Section: Introductionmentioning

confidence: 90%

“…The developing limb is a valuable model system to investigate mechanisms of gene regulation, notably due to its accessibility for manipulation and the possibility to generate limbspecific gene inactivation without impinging on embryonic survival. The function of PRC1 and PRC2 was shown to be required for proper morphogenesis of the limb along the proximal (presumptive arm) to distal (presumptive hand) axis as well as along the anterior (thumb) to posterior axis (fifth finger) [8,[11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Polycomb Repressive Complexes binding dynamics during limb development reveals the prevalence of PRC2-independent PRC1 occupancy

Gentile¹,

Mayran²,

Guerard-Millet³

et al. 2020

Preprint

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The Polycomb group (PcG) proteins are key players in the regulation of tissue-specific gene expression through their known ability to epigenetically silence developmental genes. The PcG proteins form two multicomponent complexes, Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2), whereby the hierarchical model of recruitment postulates that PRC2 triggers the trimethylation of Histone H3 lysine 27 (H3K27me3) leading to the recruitment of PRC1. Here we report on the genome-wide binding dynamics of components from both PRC1 and PRC2 in the developing limb. We show that a large proportion of PRC-bound promoters are occupied exclusively by PRC1, suggesting a more extensive PRC1-specific activity than anticipated. We found that PRC1 (RING1B) and PRC2 (SUZ12) co-occupy the promoters of developmental genes, for which a subset become up-regulated upon the inactivation of PRC2. Strikingly, we found that RING1B occupancy is largely unaffected by the loss of PRC2, revealing a complex functional relationship between these two complexes in regulating gene expression and possibly an expansive functional interplay between canonical and non-canonical PRC1.

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PRC2-Associated Chromatin Contacts in the Developing Limb Reveal a Possible Mechanism for the Atypical Role of PRC2 in HoxA Gene Expression

Cited by 34 publications

References 65 publications

The regulatory landscapes of developmental genes

The regulatory landscapes of developmental genes

Three-dimensional regulation ofHOXAcluster genes by acis-element in hematopoietic stem cell and leukemia

Analysis of Polycomb Repressive Complexes binding dynamics during limb development reveals the prevalence of PRC2-independent PRC1 occupancy

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