scholarly journals Post-transcriptional control of cellular differentiation by the RNA exosome complex

2020 ◽  
Vol 48 (21) ◽  
pp. 11913-11928
Author(s):  
Isabela Fraga de Andrade ◽  
Charu Mehta ◽  
Emery H Bresnick
Keyword(s):  
Cellular Differentiation ◽  
Transcriptional Control ◽  
Cell Type ◽  
Protein Coding ◽  
Regulatory Machinery ◽  
Regulatory Complex ◽  
Cell Type Specific ◽  
Rna Exosome ◽  
Post Transcriptional Regulation ◽  
Exosome Complex

Abstract Given the complexity of intracellular RNA ensembles and vast phenotypic remodeling intrinsic to cellular differentiation, it is instructive to consider the role of RNA regulatory machinery in controlling differentiation. Dynamic post-transcriptional regulation of protein-coding and non-coding transcripts is vital for establishing and maintaining proteomes that enable or oppose differentiation. By contrast to extensively studied transcriptional mechanisms governing differentiation, many questions remain unanswered regarding the involvement of post-transcriptional mechanisms. Through its catalytic activity to selectively process or degrade RNAs, the RNA exosome complex dictates the levels of RNAs comprising multiple RNA classes, thereby regulating chromatin structure, gene expression and differentiation. Although the RNA exosome would be expected to control diverse biological processes, studies to elucidate its biological functions and how it integrates into, or functions in parallel with, cell type-specific transcriptional mechanisms are in their infancy. Mechanistic analyses have demonstrated that the RNA exosome confers expression of a differentiation regulatory receptor tyrosine kinase, downregulates the telomerase RNA component TERC, confers genomic stability and promotes DNA repair, which have considerable physiological and pathological implications. In this review, we address how a broadly operational RNA regulatory complex interfaces with cell type-specific machinery to control cellular differentiation.

scholarly journals In vivo single-cell profiling of lncRNAs during Ebola virus infection

2022 ◽  
Author(s):  
Luisa Santus ◽  
Raquel García-Pérez ◽  
Maria Sopena-Rios ◽  
Aaron E Lin ◽  
Gordon C Adams ◽  
...  
Keyword(s):  
Viral Infection ◽  
Single Cell ◽  
Ebola Virus ◽  
Cell Type ◽  
Protein Coding ◽  
Expression Variation ◽  
Lncrna Expression ◽  
Ebov Infection ◽  
Cell Type Specific

Long non-coding RNAs (lncRNAs) are pivotal mediators of systemic immune response to viral infection, yet most studies concerning their expression and functions upon immune stimulation are limited to in vitro bulk cell populations. This strongly constrains our understanding of how lncRNA expression varies at single-cell resolution, and how their cell-type specific immune regulatory roles may differ compared to protein-coding genes. Here, we perform the first in-depth characterization of lncRNA expression variation at single-cell resolution during Ebola virus (EBOV) infection in vivo. Using bulk RNA-sequencing from 119 samples and 12 tissue types, we significantly expand the current macaque lncRNA annotation. We then profile lncRNA expression variation in immune circulating single-cells during EBOV infection and find that lncRNAs' expression in fewer cells is a major differentiating factor from their protein-coding gene counterparts. Upon EBOV infection, lncRNAs present dynamic and mostly cell-type specific changes in their expression profiles especially in monocytes, the main cell type targeted by EBOV. Such changes are associated with gene regulatory modules related to important innate immune responses such as interferon response and purine metabolism. Within infected cells, several lncRNAs have positively and negatively correlated expression with viral load, suggesting that expression of some of these lncRNAs might be directly hijacked by EBOV to attack host cells. This study provides novel insights into the roles that lncRNAs play in the host response to acute viral infection and paves the way for future lncRNA studies at single-cell resolution.

scholarly journals Characterization of novel primary miRNA transcription units in human cells using Bru-seq nascent RNA sequencing

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Karan Bedi ◽  
Michelle T Paulsen ◽  
Thomas E Wilson ◽  
Mats Ljungman
Keyword(s):  
Rna Polymerase Ii ◽  
Rna Sequencing ◽  
Regulatory Networks ◽  
Transcriptional Control ◽  
Mature Mirnas ◽  
Mirna Regulation ◽  
Cell Type ◽  
Data Resource ◽  
Cell Type Specific ◽  
Nascent Rna

Abstract MicroRNAs (miRNAs) are key contributors to gene regulatory networks. Because miRNAs are processed from RNA polymerase II transcripts, insight into miRNA regulation requires a comprehensive understanding of the regulation of primary miRNA transcripts. We used Bru-seq nascent RNA sequencing and hidden Markov model segmentation to map primary miRNA transcription units (TUs) across 32 human cell lines, allowing us to describe TUs encompassing 1443 miRNAs from miRBase and 438 from MirGeneDB. We identified TUs for 61 miRNAs with an unknown CAGE TSS signal for MirGeneDB miRNAs. Many primary transcripts containing miRNA sequences failed to generate mature miRNAs, suggesting that miRNA biosynthesis is under both transcriptional and post-transcriptional control. In addition to constitutive and cell-type specific TU expression regulated by differential promoter usage, miRNA synthesis can be regulated by transcription past polyadenylation sites (transcriptional read through) and promoter divergent transcription (PROMPTs). We identified 197 miRNA TUs with novel promoters, 97 with transcriptional read-throughs and 3 miRNA TUs that resemble PROMPTs in at least one cell line. The miRNA TU annotation data resource described here reveals a greater complexity in miRNA regulation than previously known and provides a framework for identifying cell-type specific differences in miRNA transcription in cancer and cell transition states.

scholarly journals Cis-regulatory elements of the mitotic regulator, string/Cdc25

Development ◽  
1999 ◽  
Vol 126 (9) ◽  
pp. 1793-1803 ◽  
Author(s):  
D.A. Lehman ◽  
B. Patterson ◽  
L.A. Johnston ◽  
T. Balzer ◽  
J.S. Britton ◽  
...  
Keyword(s):  
Regulatory Elements ◽  
Cell Type ◽  
Protein Coding ◽  
Cis Acting ◽  
Mitotic Kinase ◽  
Cell Type Specific ◽  
Simple Growth ◽  
Drosophila Cells ◽  
Specific Control ◽  
Control String

Mitosis in most Drosophila cells is triggered by brief bursts of transcription of string (stg), a Cdc25-type phosphatase that activates the mitotic kinase, Cdk1 (Cdc2). To understand how string transcription is regulated, we analyzed the expression of string-lacZ reporter genes covering approximately 40 kb of the string locus. We also tested protein coding fragments of the string locus of 6 kb to 31.6 kb for their ability to complement loss of string function in embryos and imaginal discs. A plethora of cis-acting elements spread over >30 kb control string transcription in different cells and tissue types. Regulatory elements specific to subsets of epidermal cells, mesoderm, trachea and nurse cells were identified, but the majority of the string locus appears to be devoted to controlling cell proliferation during neurogenesis. Consistent with this, compact promotor-proximal sequences are sufficient for string function during imaginal disc growth, but additional distal elements are required for the development of neural structures in the eye, wing, leg and notum. We suggest that, during evolution, cell-type-specific control elements were acquired by a simple growth-regulated promoter as a means of coordinating cell division with developmental processes, particularly neurogenesis.

scholarly journals Genome-wide heritability analysis of severe malaria susceptibility and resistance reveals evidence of polygenic inheritance

2019 ◽  
Author(s):  
Delesa Damena ◽  
Emile R. Chimusa
Keyword(s):  
Severe Malaria ◽  
Genome Wide Association Study ◽  
Summary Statistics ◽  
Cell Type ◽  
Protein Coding ◽  
Polygenic Inheritance ◽  
Genome Wide ◽  
Cell Type Specific ◽  
Malaria Susceptibility ◽  
Susceptibility And Resistance

ABSTRACTObjectiveEstimating SNP-heritability (h2g) of severe malaria/resistance and its distribution across the genome might shed new light in to the underlying biology.MethodWe investigated h2g of severe malaria susceptibility and resistance from genome-wide association study (GWAS) dataset (sample size =11, 657). We partitioned the h2g in to chromosomes, allele frequencies and annotations. We further examined none-cell type specific and cell type specific enrichments from GWAS-summary statistics.ResultsWe estimated the h2g of severe malaria at 0.21 (se=0.05, p=2.7×10−5), 0.20 (se =0.05, p=7.5×10−5) and 0.17 (se =0.05, p= 7.2×10−4) in Gambian, Kenyan and Malawi populations, respectively. The h2g attributed to the GWAS significant SNPs and the well-known sickle cell (HbS) variant was approximately 0.07 and 0.03, respectively. We prepared African population reference panel and obtained comparable h2g estimate (0.21 (se = 0.02, p< 1×10−5)) from GWAS-summary statistics meta-analysed across the three populations. Partitioning analysis from raw genotype data showed significant enrichment of h2g in protein coding genic SNPs while summary statistics analysis suggests pattern of enrichment in multiple categories.ConclusionWe report for the first time that the heritability of malaria susceptibility and resistance is largely ascribed by common SNPs and the causal variants are overrepresented in protein coding regions of the genome. Overall, our results suggest that malaria susceptibility and resistance is a polygenic trait. Further studies with larger sample sizes are needed to better understand the underpinning genetics of resistance and susceptibility to severe malaria.

scholarly journals Super interactive promoters provide insight into cell type-specific regulatory networks in blood lineage cell types

2021 ◽  
Author(s):  
Taylor M. Lagler ◽  
Yuchen Yang ◽  
Yuriko Harigaya ◽  
Vijay G. Sankaran ◽  
Ming Hu ◽  
...  
Keyword(s):  
Blood Cell ◽  
Regulatory Networks ◽  
Transcriptional Control ◽  
Spatial Organization ◽  
Cell Types ◽  
Gene Promoters ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific ◽  
Insight Into

Existing studies of chromatin conformation have primarily focused on potential enhancers interacting with gene promoters. By contrast, the interactivity of promoters per se, while equally critical to understanding transcriptional control, has been largely unexplored, particularly in a cell type-specific manner for blood lineage cell types. In this study, we leverage promoter capture Hi-C data across a compendium of blood lineage cell types to identify and characterize cell type-specific super-interactive promoters (SIPs). Notably, promoter-interacting regions (PIRs) of SIPs are more likely to overlap with cell type-specific ATAC-seq peaks and GWAS variants for relevant blood cell traits than PIRs of non-SIPs. Further, SIP genes tend to express at a higher level in the corresponding cell type, and show enriched heritability of relevant blood cell trait(s). Importantly, this analysis shows the potential of using promoter-centric analyses of chromatin spatial organization data to identify biologically important genes and their regulatory regions.

scholarly journals Locus- and cell type-specific epigenetic switching during cellular differentiation in mammals

2016 ◽  
Vol 11 (4) ◽  
pp. 311-322 ◽  
Author(s):  
Ying-Tao Zhao ◽  
Maria Fasolino ◽  
Zhaolan Zhou
Keyword(s):  
Cellular Differentiation ◽  
Cell Type ◽  
Cell Type Specific

scholarly journals Spatiotemporal dynamics of SETD5-containing NCoR–HDAC3 complex determines enhancer activation for adipogenesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yoshihiro Matsumura ◽  
Ryo Ito ◽  
Ayumu Yajima ◽  
Rei Yamaguchi ◽  
Toshiya Tanaka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Ubiquitin Ligase ◽  
Cellular Differentiation ◽  
Specific Gene ◽  
Cell Type ◽  
Set Domain ◽  
Protein Levels ◽  
Primed State ◽  
Cell Type Specific

AbstractEnhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated “primed” state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation. SETD5 protein levels were transiently increased and rapidly degraded prior to enhancer activation providing a mechanism for the loss of SETD5 during the transition. We show that induction of the CDC20 co-activator of the ubiquitin ligase leads to APC/C mediated degradation of SETD5 during the transition and this operates as a molecular switch that facilitates adipogenesis.

scholarly journals The Mechanism of GT Element-mediated Cell Type-specific Transcriptional Control

1996 ◽  
Vol 271 (51) ◽  
pp. 32593-32598 ◽  
Author(s):  
Patricia Villain ◽  
Régis Mache ◽  
Dao-Xiu Zhou
Keyword(s):  
Transcriptional Control ◽  
Cell Type ◽  
Cell Type Specific ◽  
Gt Element

scholarly journals Human Endogenous Retroviral Long Terminal Repeat Sequences as Cell Type-Specific Promoters in Retroviral Vectors

2009 ◽  
Vol 83 (23) ◽  
pp. 12643-12650 ◽  
Author(s):  
Ulrike Schön ◽  
Olivia Diem ◽  
Laura Leitner ◽  
Walter H. Günzburg ◽  
Dixie L. Mager ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Leukemia Virus ◽  
Cell Types ◽  
Retroviral Vectors ◽  
Endogenous Retrovirus ◽  
Human Endogenous Retrovirus ◽  
Cell Type ◽  
Specific Expression ◽  
Hybrid Vectors ◽  
Cell Type Specific

ABSTRACT The human genome contains more than half a million human endogenous retrovirus (HERV) long terminal repeats (LTRs) that can be regarded as mobile regulatory modules. Many of these HERV LTRs have been recruited during evolution as transcriptional control elements for cellular gene expression. We have cloned LTR sequences from two HERV families, HERV-H and HERV-L, differing widely in their activity and tissue specificity into a murine leukemia virus (MLV)-based promoter conversion vector (ProCon). Various human cell lines were infected with the HERV-MLV hybrid vectors, and cell type-specific expression of the reporter gene was compared with the promoter specificity of the corresponding HERV LTRs in transient-transfection assays. Transcription start site analysis of HERV-MLV hybrid vectors revealed preferential use of the HERV promoter initiation site. Our data show that HERV LTRs function in the context of retroviral vectors in certain cell types and have the potential to be useful as cell type-specific promoters in vector construction.

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