Drosha Regulates Gene Expression Independently of RNA Cleavage Function

Gromak, Natalia; Dienstbier, Martin; Macías, Sara; Plass, Mireya; Eyras, Eduardo; Cáceres, Javier F.; Proudfoot, Nick J.

doi:10.1016/j.celrep.2013.11.032

Cited by 66 publications

(66 citation statements)

References 42 publications

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“…By contrast, HP1BP3-GFP was enriched at 9,149 islands across the genome, suggesting a different chromatin binding mode from that of H1.5-GFP. Similarly, Drosha-GFP was enriched at 5,814 islands, including many non-miRNA loci, which was consistent with previous reports that Drosha could also cleave mRNA with long hairpins and regulate other biological processes (Gromak et al, 2013; Han et al, 2009; Kadener et al, 2009; Knuckles et al, 2012). …”

Section: Resultssupporting

confidence: 91%

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HP1BP3, a Chromatin Retention Factor for Co-transcriptional MicroRNA Processing

et al. 2016

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SUMMARY Recent studies suggest that the Microprocessor (Drosha-DGCR8) complex can be recruited to chromatin to catalyze co-transcriptional processing of primary microRNAs (pri-miRNAs) in mammalian cells. However, the molecular mechanism of co-transcriptional miRNA processing is poorly understood. Here, we find that HP1BP3, a histone H1-like chromatin protein, specifically associates with the Microprocessor and promotes global miRNA biogenesis in human cells. Chromatin immunoprecipitation (ChIP) studies reveal genome-wide co-localization of HP1BP3 and Drosha and HP1BP3-dependent Drosha binding to actively transcribed miRNA loci. Moreover, HP1BP3 specifically binds endogenous pri-miRNAs and facilitates the Drosha/pri-miRNA association in vivo. Knockdown of HP1BP3 compromises pri-miRNA processing by causing premature release of pri-miRNAs from the chromatin. Taken together, these studies suggest that HP1BP3 promotes co-transcriptional miRNA processing via chromatin retention of nascent pri-miRNA transcripts. This work significantly expands the functional repertoire of the H1 family of proteins and suggests the existence of chromatin retention factors for widespread co-transcriptional miRNA processing.

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Section: Resultssupporting

confidence: 91%

“…Previous studies have examined chromatin binding of Drosha or DGCR8 proteins at a few miRNA genes (Gromak et al, 2013; Morlando et al, 2008; Pawlicki and Steitz, 2008). Thus, it is uncertain whether all pri-miRNAs undergo co-transcriptional miRNA processing.…”

Section: Resultsmentioning

confidence: 99%

HP1BP3, a Chromatin Retention Factor for Co-transcriptional MicroRNA Processing

et al. 2016

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“…Although Drosha and Pasha/DGCR8 seemingly have additional non-miRNA substrates Gromak et al, 2013;Kim et al, 2017;Macias et al, 2012;Rybak-Wolf et al, 2014;Triboulet et al, 2009), the fact that removal of different components that overlap with the canonical miRNA pathway causes similar effects strongly suggests that canonical miRNAs as a whole play indispensable roles during embryonic development in animals. By contrast, the deletion of many individual miRNAs seems to cause no or only subtle defects at the level of the whole organism (Chen et al, 2014;Kloosterman et al, 2007;Miska et al, 2007;Park et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A framework for understanding the roles of miRNAs in animal development

2017

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MicroRNAs (miRNAs) contribute to the progressive changes in gene expression that occur during development. The combined loss of all miRNAs results in embryonic lethality in all animals analyzed, illustrating the crucial role that miRNAs play collectively. However, although the loss of some individual miRNAs also results in severe developmental defects, the roles of many other miRNAs have been challenging to uncover. This has been mostly attributed to their proposed function as tuners of gene expression or providers of robustness. Here, we present a view of miRNAs in the context of development as a hierarchical and canalized series of gene regulatory networks. In this scheme, only a fraction of embryonic miRNAs act at the top of this hierarchy, with their loss resulting in broad developmental defects, whereas most other miRNAs are expressed with high cellular specificity and play roles at the periphery of development, affecting the terminal features of specialized cells. This view could help to shed new light on our understanding of miRNA function in development, disease and evolution.

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“…For example, Drosha directly associates with a hairpin structure within target mRNAs, leading to their cleavage and degradation (11, 12). Drosha also associates with the promoter- proximal regions of genes and regulates their transcription (13). …”

Section: Introductionmentioning

confidence: 99%

Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia

et al. 2018

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The transforming growth factor–β (TGF-β) and bone morphogenetic protein (BMP) family of cytokines critically regulates vascular morphogenesis and homeostasis. Impairment of TGF-β or BMP signaling leads to heritable vascular disorders, including hereditary hemorrhagic telangiectasia (HHT). Drosha, a key enzyme for microRNA (miRNA) biogenesis, also regulates the TGF-β and BMP pathway through interaction with Smads and their joint control of gene expression through miRNAs. We report that mice lacking Drosha in the vascular endothelium developed a vascular phenotype resembling HHT that included dilated and disorganized vasculature, arteriovenous fistulae, and hemorrhages. Exome sequencing of HHT patients who lacked known pathogenic mutations revealed an over-representation of rare nonsynonymous variants of DROSHA. Two of these DROSHA variants (P100L and R279L) did not interact with Smads and were partially catalytically active. In zebrafish, expression of these mutants or morpholino- directed knockdown of Drosha resulted in angiogenesis defects and abnormal vascular permeability. Together, our studies point to an essential role of Drosha in vascular development and the maintenance of vascular integrity, and reveal a previously unappreciated link between Drosha dysfunction and HHT.

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Drosha Regulates Gene Expression Independently of RNA Cleavage Function

Cited by 66 publications

References 42 publications

HP1BP3, a Chromatin Retention Factor for Co-transcriptional MicroRNA Processing

HP1BP3, a Chromatin Retention Factor for Co-transcriptional MicroRNA Processing

A framework for understanding the roles of miRNAs in animal development

Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia

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