scholarly journals The SAM domain-containing protein 1 (SAMD1) acts as a repressive chromatin regulator at unmethylated CpG islands

2021 ◽  
Vol 7 (20) ◽  
pp. eabf2229
Author(s):  
Bastian Stielow ◽  
Yuqiao Zhou ◽  
Yinghua Cao ◽  
Clara Simon ◽  
Hans-Martin Pogoda ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Cpg Islands ◽  
Winged Helix ◽  
Sam Domain ◽  
Genome Wide ◽  
Chromatin Regulator ◽  
A Genome ◽  
Dna Elements ◽  
Regulatory Dna ◽  
Winged Helix Domain

CpG islands (CGIs) are key regulatory DNA elements at most promoters, but how they influence the chromatin status and transcription remains elusive. Here, we identify and characterize SAMD1 (SAM domain-containing protein 1) as an unmethylated CGI-binding protein. SAMD1 has an atypical winged-helix domain that directly recognizes unmethylated CpG-containing DNA via simultaneous interactions with both the major and the minor groove. The SAM domain interacts with L3MBTL3, but it can also homopolymerize into a closed pentameric ring. At a genome-wide level, SAMD1 localizes to H3K4me3-decorated CGIs, where it acts as a repressor. SAMD1 tethers L3MBTL3 to chromatin and interacts with the KDM1A histone demethylase complex to modulate H3K4me2 and H3K4me3 levels at CGIs, thereby providing a mechanism for SAMD1-mediated transcriptional repression. The absence of SAMD1 impairs ES cell differentiation processes, leading to misregulation of key biological pathways. Together, our work establishes SAMD1 as a newly identified chromatin regulator acting at unmethylated CGIs.

scholarly journals Novel susceptibility variants at the ERG locus for childhood acute lymphoblastic leukemia in Hispanics

Blood ◽  
2019 ◽  
Vol 133 (7) ◽  
pp. 724-729 ◽  
Author(s):  
Maoxiang Qian ◽  
Heng Xu ◽  
Virginia Perez-Andreu ◽  
Kathryn G. Roberts ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Native American ◽  
Acute Lymphoblastic Leukemia ◽  
Genome Wide Association Study ◽  
Lymphoblastic Leukemia ◽  
Causal Variant ◽  
Risk Alleles ◽  
Genome Wide ◽  
A Genome ◽  
Dna Elements ◽  
Regulatory Dna

Abstract Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Characterized by high levels of Native American ancestry, Hispanics are disproportionally affected by this cancer with high incidence and inferior survival. However, the genetic basis for this disparity remains poorly understood because of a paucity of genome-wide investigation of ALL in Hispanics. Performing a genome-wide association study (GWAS) in 940 Hispanic children with ALL and 681 ancestry-matched non-ALL controls, we identified a novel susceptibility locus in the ERG gene (rs2836365; P = 3.76 × 10−8; odds ratio [OR] = 1.56), with independent validation (P = .01; OR = 1.43). Imputation analyses pointed to a single causal variant driving the association signal at this locus overlapping with putative regulatory DNA elements. The effect size of the ERG risk variant rose with increasing Native American genetic ancestry. The ERG risk genotype was underrepresented in ALL with the ETV6-RUNX1 fusion (P < .0005) but enriched in the TCF3-PBX1 subtype (P < .05). Interestingly, ALL cases with germline ERG risk alleles were significantly less likely to have somatic ERG deletion (P < .05). Our results provide novel insights into genetic predisposition to ALL and its contribution to racial disparity in this cancer.

scholarly journals An inducible CRISPR interference library for genetic interrogation of Saccharomyces cerevisiae biology

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Amir Momen-Roknabadi ◽  
Panos Oikonomou ◽  
Maxwell Zegans ◽  
Saeed Tavazoie
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Transcriptional Repression ◽  
Nucleosome Occupancy ◽  
Design Parameters ◽  
Experimental Conditions ◽  
Crispr Interference ◽  
Cellular Processes ◽  
Genome Wide ◽  
Reliable Assessment ◽  
A Genome

AbstractGenome-scale CRISPR interference (CRISPRi) is widely utilized to study cellular processes in a variety of organisms. Despite the dominance of Saccharomyces cerevisiae as a model eukaryote, an inducible genome-wide CRISPRi library in yeast has not yet been presented. Here, we present a genome-wide, inducible CRISPRi library, based on spacer design rules optimized for S. cerevisiae. We have validated this library for genome-wide interrogation of gene function across a variety of applications, including accurate discovery of haploinsufficient genes and identification of enzymatic and regulatory genes involved in adenine and arginine biosynthesis. The comprehensive nature of the library also revealed refined spacer design parameters for transcriptional repression, including location, nucleosome occupancy and nucleotide features. CRISPRi screens using this library can identify genes and pathways with high precision and a low false discovery rate across a variety of experimental conditions, enabling rapid and reliable assessment of genetic function and interactions in S. cerevisiae.

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.

Identification of SUMO-dependent chromatin-associated transcriptional repression components by a genome-wide RNA interference screen

2008 ◽  
Vol 2008 (Spring) ◽  
Author(s):  
Guntram Suske ◽  
Bastian Stielow ◽  
Alexandra Sapetschnig ◽  
Imme Krüger ◽  
Michael Boutros
Keyword(s):  
Rna Interference ◽  
Transcriptional Repression ◽  
Genome Wide ◽  
A Genome

scholarly journals Induction of theCandida albicansFilamentous Growth Program by Relief of Transcriptional Repression: A Genome-wide Analysis

2005 ◽  
Vol 16 (6) ◽  
pp. 2903-2912 ◽  
Author(s):  
David Kadosh ◽  
Alexander D. Johnson
Keyword(s):  
Candida Albicans ◽  
Transcriptional Repression ◽  
Fungal Pathogen ◽  
Morphological Transition ◽  
Whole Genome ◽  
Transcriptional Repressors ◽  
Genome Wide Analysis ◽  
Human Fungal Pathogen ◽  
Genome Wide ◽  
A Genome

Candida albicans, the major human fungal pathogen, undergoes a reversible morphological transition from blastospores (round budding cells) to filaments (elongated cells attached end-to-end). This transition, which is induced upon exposure of C. albicans cells to a number of host conditions, including serum and body temperature (37°C), is required for virulence. Using whole-genome DNA microarray analysis, we describe 61 genes that are significantly induced (≥2-fold) during the blastospore to filament transition that takes place in response to exposure to serum and 37°C. We next show that approximately half of these genes are transcriptionally repressed in the blastospore state by three transcriptional repressors, Rfg1, Nrg1, and Tup1. We conclude that the relief of this transcriptional repression plays a key role in bringing the C. albicans filamentous growth program into play, and we describe the framework of this transcriptional circuit.

scholarly journals DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease

2017 ◽  
Vol 114 (36) ◽  
pp. E7526-E7535 ◽  
Author(s):  
Danuta M. Jeziorska ◽  
Robert J. S. Murray ◽  
Marco De Gobbi ◽  
Ricarda Gaentzsch ◽  
David Garrick ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cpg Islands ◽  
Naturally Occurring ◽  
Genome Wide ◽  
A Genome ◽  
Primary Determinant ◽  
Development And Differentiation ◽  
Intrinsic Capacity

The human genome contains ∼30,000 CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 CGIs lying within gene bodies become methylated during development and differentiation. Both promoter and intragenic CGIs may also become abnormally methylated as a result of genome rearrangements and in malignancy. The epigenetic mechanisms by which some CGIs become methylated but others, in the same cell, remain unmethylated in these situations are poorly understood. Analyzing specific loci and using a genome-wide analysis, we show that transcription running across CGIs, associated with specific chromatin modifications, is required for DNA methyltransferase 3B (DNMT3B)-mediated DNA methylation of many naturally occurring intragenic CGIs. Importantly, we also show that a subgroup of intragenic CGIs is not sensitive to this process of transcription-mediated methylation and that this correlates with their individual intrinsic capacity to initiate transcription in vivo. We propose a general model of how transcription could act as a primary determinant of the patterns of CGI methylation in normal development and differentiation, and in human disease.

scholarly journals DNA sequence models of genome-wide Drosophila melanogaster Polycomb binding sites improve generalization to independent Polycomb Response Elements

2019 ◽  
Vol 47 (15) ◽  
pp. 7781-7797 ◽  
Author(s):  
Bjørn André Bredesen ◽  
Marc Rehmsmeier
Keyword(s):  
Drosophila Melanogaster ◽  
Sequence Similarity ◽  
Sequence Motifs ◽  
Chromatin Binding ◽  
Training Set ◽  
Response Elements ◽  
Genome Wide ◽  
Dna Elements ◽  
Polycomb Response Elements ◽  
Regulatory Dna

Abstract Polycomb Response Elements (PREs) are cis-regulatory DNA elements that maintain gene transcription states through DNA replication and mitosis. PREs have little sequence similarity, but are enriched in a number of sequence motifs. Previous methods for modelling Drosophila melanogaster PRE sequences (PREdictor and EpiPredictor) have used a set of 7 motifs and a training set of 12 PREs and 16-23 non-PREs. Advances in experimental methods for mapping chromatin binding factors and modifications has led to the publication of several genome-wide sets of Polycomb targets. In addition to the seven motifs previously used, PREs are enriched in the GTGT motif, recently associated with the sequence-specific DNA binding protein Combgap. We investigated whether models trained on genome-wide Polycomb sites generalize to independent PREs when trained with control sequences generated by naive PRE models and including the GTGT motif. We also developed a new PRE predictor: SVM-MOCCA. Training PRE predictors with genome-wide experimental data improves generalization to independent data, and SVM-MOCCA predicts the majority of PREs in three independent experimental sets. We present 2908 candidate PREs enriched in sequence and chromatin signatures. 2412 of these are also enriched in H3K4me1, a mark of Trithorax activated chromatin, suggesting that PREs/TREs have a common sequence code.

scholarly journals Nuclease deficiencies alter plasma cell-free DNA methylation profiles

2021 ◽  
pp. gr.275426.121
Author(s):  
Diana Siao Cheng Han ◽  
Meng Ni ◽  
Rebecca Wing Yan Chan ◽  
Danny Ka Lok Wong ◽  
Linda T Hiraki ◽  
...  
Keyword(s):  
Fragment Size ◽  
Cpg Islands ◽  
Periodic Pattern ◽  
Open Chromatin ◽  
Cell Free Dna ◽  
Free Dna ◽  
Genome Wide ◽  
A Genome ◽  
Wide Scale ◽  
Deficient Mice

The effects of DNASE1L3 or DNASE1 deficiency on cell-free DNA (cfDNA) methylation was explored in plasma of mice deficient in these nucleases and in DNASE1L3-deficient humans. Compared to wild-type cfDNA, cfDNA in Dnase1l3-deficient mice was significantly hypomethylated, while cfDNA in Dnase1-deficient mice was hypermethylated. The cfDNA hypomethylation in Dnase1l3-deficient mice was due to increased fragmentation and representation from open chromatin regions (OCRs) and CpG islands (CGIs). These findings were absent in Dnase1-deficient mice, demonstrating the preference of DNASE1 to cleave in hypomethylated OCRs and CGIs. We also observed a substantial decrease of fragment ends and coverage at methylated CpGs in the absence of DNASE1L3, thereby demonstrating that DNASE1L3 prefers to cleave at methylated CpGs. Furthermore, we found that methylation levels of cfDNA varied by fragment size in a periodic pattern, with cfDNA of specific sizes being more hypomethylated and enriched for OCRs and CGIs. These findings were confirmed in DNASE1L3-deficient human cfDNA. Thus, we have found that nuclease-mediated cfDNA fragmentation markedly affected cfDNA methylation level on a genome-wide scale. This work provides a foundational understanding of the relationship between methylation, nuclease biology and cfDNA fragmentation.

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