scholarly journals PRC1 sustains the integrity of neural fate in the absence of PRC2 function

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Ayana Sawai ◽  
Sarah Pfennig ◽  
Milica Bulajić ◽  
Alexander Miller ◽  
Alireza Khodadadi-Jamayran ◽  
...  
Keyword(s):  
De Novo ◽  
Ectopic Expression ◽  
Chromatin Accessibility ◽  
Spinal Motor Neuron ◽  
Neural Fate ◽  
Neuronal Fate ◽  
Spinal Motor ◽  
Broad Variety ◽  
Neuronal Subtype ◽  
Polycomb Repressive Complexes

Polycomb repressive complexes (PRCs) 1 and 2 maintain stable cellular memories of early fate decisions by establishing heritable patterns of gene repression. PRCs repress transcription through histone modifications and chromatin compaction, but their roles in neuronal subtype diversification are poorly defined. We found that PRC1 is essential for the specification of segmentally-restricted spinal motor neuron (MN) subtypes, while PRC2 activity is dispensable to maintain MN positional identities during terminal differentiation. Mutation of the core PRC1 component Ring1 in mice leads to increased chromatin accessibility and ectopic expression of a broad variety of fates determinants, including Hox transcription factors, while neuronal class-specific features are maintained. Loss of MN subtype identities in Ring1 mutants is due to the suppression of Hox-dependent specification programs by derepressed Hox13 paralogs (Hoxa13, Hoxb13, Hoxc13, Hoxd13). These results indicate that PRC1 can function in the absence of de novo PRC2-dependent histone methylation to maintain chromatin topology and postmitotic neuronal fate.

scholarly journals PRC1 Sustains the Memory of Neuronal Fate Independent of PRC2 Function

2021 ◽  
Author(s):  
Jeremy Dasen ◽  
Ayana Sawai ◽  
Sarah Pfennig ◽  
Milica Bulajić ◽  
Alexander Miller ◽  
...  
Keyword(s):  
Motor Neurons ◽  
De Novo ◽  
Ectopic Expression ◽  
Chromatin Accessibility ◽  
Spinal Motor Neurons ◽  
Neuronal Fate ◽  
Transcriptional Memory ◽  
Broad Variety ◽  
Neuronal Subtype ◽  
Polycomb Repressive Complexes

Polycomb repressive complexes (PRCs) 1 and 2 maintain stable cellular memories of early fate decisions by establishing heritable patterns of gene repression. PRCs repress transcription through histone modifications and chromatin compaction, but their roles in neuronal subtype diversification are poorly defined. We unexpectedly found that PRC2 is dispensable to preserve the morphogen-induced positional fates of spinal motor neurons (MNs), while PRC1 is essential for the specification of segmentally-restricted subtypes. Mutation of the core PRC1 component Ring1 in mice leads to increased chromatin accessibility and ectopic expression of a broad variety of fates determinants, including Hox transcription factors, while neuronal class-specific features are maintained. Loss of MN subtype identities in Ring1 mutants is due to the suppression of Hox networks by derepressed caudal Hox genes. These results indicate that PRC1 can function independently of de novo PRC2-dependent histone methylation to maintain chromatin topology and transcriptional memory at the time of neuronal differentiation.

scholarly journals Efficient hemogenic endothelial cell specification by RUNX1 is dependent on baseline chromatin accessibility of RUNX1-regulated TGFβ target genes

2021 ◽  
Author(s):  
Elizabeth D. Howell ◽  
Amanda D. Yzaguirre ◽  
Peng Gao ◽  
Raphael Lis ◽  
Bing He ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Target Genes ◽  
De Novo ◽  
Ectopic Expression ◽  
Chromatin Accessibility ◽  
Tgfβ Signaling ◽  
Hematopoietic Stem ◽  
Mesenchymal Transition ◽  
Stem And Progenitor Cells ◽  
Endothelial To Mesenchymal Transition

Hematopoietic stem and progenitor cells (HSPCs) are generated de novo in the embryo from hemogenic endothelial cells (HECs) via an endothelial-to-hematopoietic transition (EHT) that requires the transcription factor RUNX1. Ectopic expression of RUNX1 alone can efficiently promote EHT and HSPC formation from embryonic endothelial cells (ECs), but less efficiently from fetal or adult ECs. Efficiency correlated with baseline accessibility of TGFβ-related genes associated with endothelial-to-mesenchymal transition (EndoMT) and participation of AP-1 and SMAD2/3 to initiate further chromatin remodeling along with RUNX1 at these sites. Activation of TGFβ signaling improved the efficiency with which RUNX1 specified fetal ECs as HECs. Thus, the ability of RUNX1 to promote EHT depends on its ability to recruit the TGFβ signaling effectors AP-1 and SMAD2/3, which in turn is determined by the changing chromatin landscape in embryonic versus fetal ECs. This work provides insight into regulation of EndoMT and EHT that will guide reprogramming efforts for clinical applications.

scholarly journals Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jaime Alvarez-Benayas ◽  
Nikolaos Trasanidis ◽  
Alexia Katsarou ◽  
Kanagaraju Ponnusamy ◽  
Aristeidis Chaidos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Regulatory Networks ◽  
Plasma Cells ◽  
De Novo ◽  
Ectopic Expression ◽  
Transcriptome Profiling ◽  
Myeloma Cell ◽  
Chromatin Accessibility ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact

AbstractMultiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myeloma initiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia.

scholarly journals Over-accessible chromatin links myeloma initiating genetic events to oncogenic transcriptomes and aberrant transcription factor regulatory networks

2020 ◽  
Author(s):  
Jaime Alvarez-Benayas ◽  
Alexia Katsarou ◽  
Nikolaos Trasanidis ◽  
Aristeidis Chaidos ◽  
Philippa C May ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Plasma Cells ◽  
De Novo ◽  
Ectopic Expression ◽  
Transcriptome Profiling ◽  
Regulatory Elements ◽  
Myeloma Cell ◽  
Chromatin Accessibility ◽  
Bone Marrow Plasma ◽  
Genetic Events

Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Myeloma initiating genetic events define subgroups (MIE) and drive distinct oncogenic transcriptomes that converge into a mutually exclusive overexpression of CCND1 and CCND2 oncogenes. Here, with reference to normal PC, we dissect how MIE impact the chromatin regulatory landscape of MM. We find that chromatin accessibility combined with transcriptome profiling classifies myeloma genetic subgroups, while in a topologically constrained manner, distal rather than proximal regulatory elements influence myeloma transcriptomes. Across and within MIE-defined subgroups, genes and pathways critical for myeloma biology can be linked to developmentally activated or de novo formed enhancers. We show that existing transcription factors, co-opted to organise highly ordered, aberrant regulatory networks, generate known and novel myeloma cell dependencies and help identify prognostic markers. Finally, we discover and functionally validate the critical enhancer that regulates ectopic expression of CCND2 in MM.

scholarly journals ASC proneural transcription factors mediate the timely initiation of the neural program during neuroectodermal to neuroblast transition ensuring progeny fidelity

2021 ◽  
Author(s):  
Vasiliki Theodorou ◽  
Aikaterini Stefanaki ◽  
Minas Drakos ◽  
Dafne Triantafyllou ◽  
Christos Delidakis
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cis Elements ◽  
Enhancer Activity ◽  
Timely Initiation ◽  
Chromatin Dynamics ◽  
Neural Fate ◽  
Neural Specification

Background: ASC/ASCL proneural transcription factors are oncogenic and exhibit impressive reprogramming and pioneer activities. In both Drosophila and mammals, these factors are central in the early specification of the neural fate, where they act in opposition to Notch signalling. However, the role of ASC on the chromatin during CNS neural stem cells birth remains elusive. Results: We investigated the chromatin changes accompanying neural commitment using an integrative genetics and genomics methodology. We found that ASC factors bind equally strongly to two distinct classes of cis-regulatory elements: open regions remodeled earlier during maternal to zygotic transition by Zelda and Zelda-independent, less accessible regions. Both classes cis-elements exhibit enhanced chromatin accessibility during neural specification and correlate with transcriptional regulation of genes involved in many biological processes necessary for neuroblast function. We identified an ASC-Notch regulated TF network that most likely act as the prime regulators of neuroblast function. Using a cohort of ASC target genes, we report that ASC null neuroblasts are defectively specified, remaining initially stalled, lacking expression of many proneural targets and unable to divide. When they eventually start proliferating, they produce compromised progeny. Generation of lacZ reporter lines driven by proneural-bound elements display enhancer activity within neuroblasts and proneural dependency. Therefore, the partial neuroblast identity seen in the absence of ASC genes is driven by other, proneural-independent, cis-elements. Neuroblast impairment and the late differentiation defects of ASC mutants are corrected by ectodermal induction of individual ASC genes but not by individual members of the TF network downstream of ASC. However, in wild type embryos induction of individual members of this network induces CNS hyperplasia, suggesting that they synergize with the activating function of ASC to establish the chromatin dynamics that promote neural specification. Conclusion: ASC factors bind a large number of enhancers to orchestrate the timely activation of the neural chromatin program during neuroectodermal to neuroblast transition. This early chromatin remodeling is crucial for both neuroblast homeostasis as well as future progeny fidelity.

scholarly journals LANA-Mediated Recruitment of Host Polycomb Repressive Complexes onto the KSHV Genome during De Novo Infection

2016 ◽  
Vol 12 (9) ◽  
pp. e1005878 ◽  
Author(s):  
Zsolt Toth ◽  
Bernadett Papp ◽  
Kevin Brulois ◽  
Youn Jung Choi ◽  
Shou-Jiang Gao ◽  
...  
Keyword(s):  
De Novo ◽  
Polycomb Repressive Complexes
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