scholarly journals Genome-Wide Distribution of MacroH2A1 Histone Variants in Mouse Liver Chromatin

2010 ◽  
Vol 30 (23) ◽  
pp. 5473-5483 ◽  
Author(s):  
Lakshmi N. Changolkar ◽  
Geetika Singh ◽  
Kairong Cui ◽  
Joel B. Berletch ◽  
Keji Zhao ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Histone Variants ◽  
Wide Distribution ◽  
X Inactivation ◽  
Local Concentration ◽  
Inactive X Chromosome ◽  
Genome Wide ◽  
A Genome ◽  
High Throughput Dna Sequencing ◽  
Liver Chromatin

ABSTRACT Studies of macroH2A histone variants indicate that they have a role in regulating gene expression. To identify direct targets of the macroH2A1 variants, we produced a genome-wide map of the distribution of macroH2A1 nucleosomes in mouse liver chromatin using high-throughput DNA sequencing. Although macroH2A1 nucleosomes are widely distributed across the genome, their local concentration varies over a range of 100-fold or more. The transcribed regions of most active genes are depleted of macroH2A1, often in sharply localized domains that show depletion of 4-fold or more relative to bulk mouse liver chromatin. We used macroH2A1 enrichment to help identify genes that appear to be directly regulated by macroH2A1 in mouse liver. These genes functionally cluster in the area of lipid metabolism. All but one of these genes has increased expression in macroH2A1 knockout mice, indicating that macroH2A1 functions primarily as a repressor in adult liver. This repressor activity is further supported by the substantial and relatively uniform macroH2A1 enrichment along the inactive X chromosome, which averages 4-fold. Genes that escape X inactivation stand out as domains of macroH2A1 depletion. The rarity of such genes indicates that few genes escape X inactivation in mouse liver, in contrast to what has been observed in human cells.

scholarly journals A genome-wide screen in the mouse liver reveals sex-specific and cell non-autonomous regulation of cell fitness

2021 ◽  
Author(s):  
Heather R. Keys ◽  
Kristin A. Knouse
Keyword(s):  
Functional Genomics ◽  
High Throughput ◽  
Mouse Liver ◽  
Ex Vivo ◽  
Screening Method ◽  
Living Organism ◽  
Cellular Processes ◽  
Autonomous Regulation ◽  
Genome Wide ◽  
A Genome

ABSTRACTOur ability to understand and modulate mammalian physiology and disease requires knowing how all genes contribute to any given phenotype in the organism. Genome-wide screening using CRISPR-Cas9 has emerged as a powerful method for the genetic dissection of cellular processes1,2, but the need to stably deliver single guide RNAs to millions of cells has restricted its implementation to ex vivo systems. These ex vivo systems cannot reproduce all of the cellular phenotypes observed in vivo nor can they recapitulate all of the factors that influence these phenotypes. There thus remains a pressing need for high-throughput functional genomics in a living organism. Here, we establish accessible genome-wide screening in the mouse liver and use this approach to uncover the complete regulation of cellular fitness in a living organism. We discover novel sex-specific and cell non-autonomous regulation of cell growth and viability. In particular, we find that the class I major histocompatibility complex is essential for preventing immune-mediated clearance of hepatocytes. Our approach provides the first comprehensive picture of cell fitness in a living organism and highlights the importance of investigating cellular phenomena in their native context. Our screening method is robust, scalable, and easily adapted to examine diverse cellular processes using any CRISPR application. We have hereby established a foundation for high-throughput functional genomics in a living mammal, enabling unprecedented insight into mammalian physiology and disease.

scholarly journals macroH2A1 Histone Variants Are Depleted on Active Genes but Concentrated on the Inactive X Chromosome

2006 ◽  
Vol 26 (12) ◽  
pp. 4410-4420 ◽  
Author(s):  
Lakshmi N. Changolkar ◽  
John R. Pehrson
Keyword(s):  
X Chromosome ◽  
Distribution Patterns ◽  
Detailed Examination ◽  
Histone Variants ◽  
Heterochromatin Protein ◽  
Inactive X Chromosome ◽  
Preferential Localization ◽  
Intergenic Regions ◽  
Liver Chromatin ◽  
Active Genes

ABSTRACT Using a novel thiol affinity chromatography approach to purify macroH2A1-containing chromatin fragments, we examined the distribution of macroH2A1 histone variants in mouse liver chromatin. We found that macroH2A1 was depleted on the transcribed regions of active genes. This depletion was observed on all of the 20 active genes that we probed, with only one site showing a small amount of enrichment. In contrast, macroH2A1 was concentrated on the inactive X chromosome, consistent with our previous immunofluorescence studies. This preferential localization was seen on genes that are active in liver, genes that are inactive in liver, and intergenic regions but was absent from four regions that escape X inactivation. These results support the hypothesis that macroH2As function as transcriptional repressors. Also consistent with this hypothesis is our finding that the heterochromatin protein HP1β copurifies with the macroH2A1-containing chromatin fragments. This study presents the first detailed examination of the distribution of macroH2A1 variants on specific sequences. Our results indicate that macroH2As have complex distribution patterns that are influenced by both local factors and long-range mechanisms.

scholarly journals Genome-wide analysis of SREBP-1 binding in mouse liver chromatin reveals a preference for promoter proximal binding to a new motif

2009 ◽  
Vol 106 (33) ◽  
pp. 13765-13769 ◽  
Author(s):  
Y.-K. Seo ◽  
H. K. Chong ◽  
A. M. Infante ◽  
S.-S. Im ◽  
X. Xie ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Liver Chromatin

Chromatin regulators: weaving epigenetic nets

2010 ◽  
Vol 1 (3-4) ◽  
pp. 225-238 ◽  
Author(s):  
Inmaculada Hernández-Muñoz
Keyword(s):  
Nucleosome Position ◽  
Histone Variants ◽  
Cellular Memory ◽  
Intrinsic Signals ◽  
Differentiated Cells ◽  
Chromatin Regulators ◽  
Genome Wide ◽  
Chromatin Regulator ◽  
A Genome ◽  
Multicellular Organisms

AbstractIn multicellular organisms differentiated cells must maintain their cellular memory, which will be faithfully inherited and maintained by their progeny. In addition, these specialized cells are exposed to specific environmental and cell-intrinsic signals and will have to appropriately respond to them. Some of these stimuli lead to changes in a subset of genes or to a genome-wide reprogramming of the cells that will remain after stimuli removal and, in some instances, will be inherited by the daughter cells. The molecular substrate that integrates cellular memory and plasticity is the chromatin, a complex of DNA and histones unique to eukaryotes. The nucleosome is the fundamental unit of the chromatin and nucleosomal organization defines different chromatin conformations. Chromatin regulators affect chromatin conformation and accessibility by covalently modifying the DNA or the histones, substituting histone variants, remodeling the nucleosome position or modulating chromatin looping and folding. These regulators frequently act in multiprotein complexes and highly specific interplays among chromatin marks and different chromatin regulators allow a remarkable array of possibilities. Therefore, chromatin regulator nets act to propagate the conformation of different chromatin regions through DNA replication and mitosis, and to remodel the chromatin fiber to regulate the accessibility of the DNA to transcription factors and to the transcription and repair machineries. Here, the state-of-the-art of the best-known chromatin regulators is reviewed.

Genome-wide abundance of 5-hydroxymethylcytosine in breast tissue reveals unique function in dynamic gene regulation and carcinogenesis

2018 ◽  
Author(s):  
Owen M. Wilkins ◽  
Kevin C. Johnson ◽  
E. Andres Houseman ◽  
Jessica E. King ◽  
Carmen J. Marsit ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Breast Tissue ◽  
Cell Function ◽  
Immune Cell ◽  
Normal Breast Tissue ◽  
Wide Distribution ◽  
Normal Breast ◽  
Lactate Oxidation ◽  
Genome Wide ◽  
A Genome

Abstract5-hydroxymethylcytosine (5hmC) is generated by oxidation of 5-methylcytosine (5mC), however little is understood regarding the distribution and functions of 5hmC in mammalian cells. We determined the genome-wide distribution of 5hmC and 5mC in normal breast tissue from disease-free women. Although less abundant than 5mC, 5hmC is differentially distributed, and consistently enriched among breast-specific enhancers and transcriptionally active chromatin. In contrast, regulatory regions associated with transcriptional inactivity were relatively depleted of 5hmC. Gene regions containing abundant 5hmC were significantly associated with lactate oxidation, immune cell function, and prolactin signaling pathways. In independent data sets, normal breast tissue 5hmC was significantly enriched among CpG loci demonstrated to have altered methylation in pre-invasive breast cancer and invasive breast tumors. Our findings provide a genome-wide map of nucleotide-level 5hmC in normal breast tissue and demonstrate that 5hmC is positioned to contribute to gene regulatory functions which protect against carcinogenesis.

scholarly journals Genome‐wide Localization of SREBP‐2 in Mouse Liver‐Chromatin by ChIP‐seq

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Young‐kyo Seo ◽  
Hansook Kim Chong ◽  
Jacob Biesinger ◽  
Xiaohui Xie ◽  
Tae‐Il Jeon ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Genome Wide ◽  
Liver Chromatin

scholarly journals Regulation of Pol II Pausing Is Involved in Daily Gene Transcription in the Mouse Liver

2018 ◽  
Vol 33 (4) ◽  
pp. 350-362 ◽  
Author(s):  
Jialou Zhu ◽  
Chengwei Li ◽  
Changxia Gong ◽  
Xiaodong Li
Keyword(s):  
Gene Transcription ◽  
Mouse Liver ◽  
Phase Distribution ◽  
Gene Body ◽  
Pol Ii ◽  
Genome Wide ◽  
A Genome ◽  
Pol Ii Pausing ◽  
Transcriptional Output

The circadian clock orchestrates gene expression rhythms. Regulation at the level of gene transcription is essential for molecular and cellular rhythms. Pol II pause release is a critical step of transcription regulation. However, whether and how Pol II pause release is regulated during daily transcription have not been characterized. In this study, we performed Pol II ChIP-seq across the day in the mouse liver and quantitatively analyzed binding signals within the transcription start site (TSS) region and the gene body. We frequently found discordant changes between Pol II near the TSS ([Pol II]TSS, paused Pol II) and that within the gene body ([Pol II]GB, transcribing Pol II) across the genome, with only [Pol II]GB always reflecting transcription of clock and clock-controlled genes. Accordingly, Pol II traveling ratios of more than 7000 genes showed significant daily changes (>1.5-fold). Therefore, there is widespread regulation of Pol II pausing in the mouse liver. Interestingly, gene transcription rhythms exhibited a bimodal phase distribution. The transcription of ~400 genes peaked near ZT0, coincident with a genome-wide increase in [Pol II]TSS and traveling ratio (TR). The transcription of ~300 other genes peaked ~12 h later, when there was a global decrease in [Pol II]TSS and TR. ChIP-seq against TATA-binding protein (Tbp), a preinitiation complex (PIC) component, revealed that Pol II recruitment mainly played an indirect role in transcriptional output, with transcriptional termination and pause release functioning prominently in determining the fate of initiated Pol II and its pausing status. Taken together, our results revealed a critical, albeit complex role of Pol II pausing control in regulating the temporal output of gene transcription.

Genome-wide identification of microRNA targets reveals positive regulation of the Hippo pathway by miR-122 during liver development

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Yin Zhang ◽  
Ye-Ya Tan ◽  
Pei-Pei Chen ◽  
Hui Xu ◽  
Shu-Juan Xie ◽  
...  
Keyword(s):  
Mouse Liver ◽  
High Throughput Sequencing ◽  
Developmental Stages ◽  
Hippo Pathway ◽  
Liver Development ◽  
Liver Size ◽  
Genome Wide ◽  
A Genome ◽  
The Hippo Pathway

AbstractLiver development is a highly complex process that is regulated by the orchestrated interplay of epigenetic regulators, transcription factors, and microRNAs (miRNAs). Owing to the lack of global in vivo targets of all miRNAs during liver development, the mechanisms underlying the dynamic control of hepatocyte differentiation by miRNAs remain elusive. Here, using Argonaute (Ago) high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) in the mouse liver at different developmental stages, we characterized massive Ago-binding RNAs and obtained a genome-wide map of liver miRNA-mRNA interactions. The dynamic changes of five clusters of miRNAs and their potential targets were identified to be differentially involved at specific stages, a dozen of high abundant miRNAs and their epigenetic regulation by super-enhancer were found during liver development. Remarkably, miR-122, a liver-specific and most abundant miRNA in newborn and adult livers, was found by its targetome and pathway reporter analyses to regulate the Hippo pathway, which is crucial for liver size control and homeostasis. Mechanistically, we further demonstrated that miR-122 negatively regulates the outcomes of the Hippo pathway transcription factor TEAD by directly targeting a number of hippo pathway regulators, including the coactivator TAZ and a key factor of the phosphatase complex PPP1CC, which contributes to the dephosphorylation of YAP, another coactivator downstream of the Hippo pathway. This study identifies for the first time the genome-wide miRNA targetomes during mouse liver development and demonstrates a novel mechanism of terminal differentiation of hepatocytes regulated by the miR-122/Hippo pathway in a coordinated manner. As the Hippo pathway plays important roles in cell proliferation and liver pathological processes like inflammation, fibrosis, and hepatocellular carcinoma (HCC), our study could also provide a new insight into the function of miR-122 in liver pathology.

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