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Artikel ; Online: Mechanistic drivers of chromatin organization into compartments.

Harris, Hannah L / Rowley, M Jordan

Current opinion in genetics & development

2024 Band 86, Seite(n) 102193

Abstract: The human genome is not just a simple string of DNA, it is a complex and dynamic entity intricately folded within the cell's nucleus. This three-dimensional organization of chromatin, the combination of DNA and proteins in the nucleus, is crucial for ... ...

Abstract	The human genome is not just a simple string of DNA, it is a complex and dynamic entity intricately folded within the cell's nucleus. This three-dimensional organization of chromatin, the combination of DNA and proteins in the nucleus, is crucial for many biological processes and has been prominently studied for its intricate relationship to gene expression. Indeed, the transcriptional machinery does not operate in isolation but interacts intimately with the folded chromatin structure. Techniques for chromatin conformation capture, including genome-wide sequencing approaches, have revealed key organizational features of chromatin, such as the formation of loops by CCCTC-binding factor (CTCF) and the division of loci into chromatin compartments. While much of the recent research and reviews have focused on CTCF loops, we discuss several new revelations that have emerged concerning chromatin compartments, with a particular focus on what is known about mechanistic drivers of compartmentalization. These insights challenge the traditional views of chromatin organization and reveal the complexity behind the formation and maintenance of chromatin compartments.
Sprache	Englisch
Erscheinungsdatum	2024-04-15
Erscheinungsland	England
Dokumenttyp	Journal Article ; Review
ZDB-ID	1077312-5
ISSN	1879-0380 ; 0959-437X
ISSN (online)	1879-0380
ISSN	0959-437X
DOI	10.1016/j.gde.2024.102193
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: HiCrayon reveals distinct layers of multi-state 3D chromatin organization.

Nolan, Ben / Harris, Hannah L / Kalluchi, Achyuth / Reznicek, Timothy E / Cummings, Christopher T / Rowley, M Jordan

bioRxiv : the preprint server for biology

2024

Abstract: The co-visualization of chromatin conformation with 1D 'omics data is key to the multi-omics driven data analysis of 3D genome organization. Chromatin contact maps are often shown as 2D heatmaps and visually compared to 1D genomic data by simple ... ...

Abstract	The co-visualization of chromatin conformation with 1D 'omics data is key to the multi-omics driven data analysis of 3D genome organization. Chromatin contact maps are often shown as 2D heatmaps and visually compared to 1D genomic data by simple juxtaposition. While common, this strategy is imprecise, placing the onus on the reader to align features with each other. To remedy this, we developed HiCrayon, an interactive tool that facilitates the integration of 3D chromatin organization maps and 1D datasets. This visualization method integrates data from genomic assays directly into the chromatin contact map by coloring interactions according to 1D signal. HiCrayon is implemented using R shiny and python to create a graphical user interface (GUI) application, available in both web or containerized format to promote accessibility. HiCrayon is implemented in R, and includes a graphical user interface (GUI), as well as a slimmed-down web-based version that lets users quickly produce publication-ready images. We demonstrate the utility of HiCrayon in visualizing the effectiveness of compartment calling and the relationship between ChIP-seq and various features of chromatin organization. We also demonstrate the improved visualization of other 3D genomic phenomena, such as differences between loops associated with CTCF/cohesin vs. those associated with H3K27ac. We then demonstrate HiCrayon's visualization of organizational changes that occur during differentiation and use HiCrayon to detect compartment patterns that cannot be assigned to either A or B compartments, revealing a distinct 3rd chromatin compartment. Overall, we demonstrate the utility of co-visualizing 2D chromatin conformation with 1D genomic signals within the same matrix to reveal fundamental aspects of genome organization. Local version: https://github.com/JRowleyLab/HiCrayon Web version: https://jrowleylab.com/HiCrayon.
Sprache	Englisch
Erscheinungsdatum	2024-02-12
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2024.02.11.579821
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Considerations and caveats for analyzing chromatin compartments.

Kalluchi, Achyuth / Harris, Hannah L / Reznicek, Timothy E / Rowley, M Jordan

Frontiers in molecular biosciences

2023 Band 10, Seite(n) 1168562

Abstract: Genomes are organized into nuclear compartments, separating active from inactive chromatin. Chromatin compartments are readily visible in a large number of species by experiments that map chromatin conformation genome-wide. When analyzing these maps, a ... ...

Abstract	Genomes are organized into nuclear compartments, separating active from inactive chromatin. Chromatin compartments are readily visible in a large number of species by experiments that map chromatin conformation genome-wide. When analyzing these maps, a common step is the identification of genomic intervals that interact within A (active) and B (inactive) compartments. It has also become increasingly common to identify and analyze subcompartments. We review different strategies to identify A/B and subcompartment intervals, including a discussion of various machine-learning approaches to predict these features. We then discuss the strengths and limitations of current strategies and examine how these aspects of analysis may have impacted our understanding of chromatin compartments.
Sprache	Englisch
Erscheinungsdatum	2023-04-05
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article ; Review
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2023.1168562
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Defining a cohort of anemia-activated cis elements reveals a mechanism promoting erythroid precursor function.

Zhou, Yichao / Dogiparthi, Venkatasai Rahul / Ray, Suhita / Schaefer, Meg A / Harris, Hannah L / Rowley, M Jordan / Hewitt, Kyle J

Blood advances

2023 Band 7, Heft 20, Seite(n) 6325–6338

Abstract: Acute anemia elicits broad transcriptional changes in erythroid progenitors and precursors. We previously discovered a cis-regulatory transcriptional enhancer at the sterile alpha motif domain-14 enhancer locus (S14E), defined by a CANNTG-spacer-AGATAA ... ...

Abstract	Acute anemia elicits broad transcriptional changes in erythroid progenitors and precursors. We previously discovered a cis-regulatory transcriptional enhancer at the sterile alpha motif domain-14 enhancer locus (S14E), defined by a CANNTG-spacer-AGATAA composite motif and occupied by GATA1 and TAL1 transcription factors, is required for survival in severe anemia. However, S14E is only 1 of dozens of anemia-activated genes containing similar motifs. In a mouse model of acute anemia, we identified populations of expanding erythroid precursors, which increased expression of genes that contain S14E-like cis elements. We reveal that several S14E-like cis elements provide important transcriptional control of newly identified anemia-inducing genes, including the Ssx-2 interacting protein (Ssx2ip). Ssx2ip expression was determined to play an important role in erythroid progenitor/precursor cell activities, cell cycle regulation, and cell proliferation. Over a weeklong course of acute anemia recovery, we observed that erythroid gene activation mediated by S14E-like cis elements occurs during a phase coincident with low hematocrit and high progenitor activities, with distinct transcriptional programs activated at earlier and later time points. Our results define a genome-wide mechanism in which S14E-like enhancers control transcriptional responses during erythroid regeneration. These findings provide a framework to understand anemia-specific transcriptional mechanisms, ineffective erythropoiesis, anemia recovery, and phenotypic variability within human populations.
Sprache	Englisch
Erscheinungsdatum	2023-02-21
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2022009163
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Predicting A/B compartments from histone modifications using deep learning.

Zheng, Suchen / Thakkar, Nitya / Harris, Hannah L / Liu, Susanna / Zhang, Megan / Gerstein, Mark / Aiden, Erez Lieberman / Rowley, M Jordan / Noble, William Stafford / Gürsoy, Gamze / Singh, Ritambhara

iScience

2024 Band 27, Heft 5, Seite(n) 109570

Abstract: The three-dimensional organization of genomes plays a crucial role in essential biological processes. The segregation of chromatin into A and B compartments highlights regions of activity and inactivity, providing a window into the genomic activities ... ...

Abstract	The three-dimensional organization of genomes plays a crucial role in essential biological processes. The segregation of chromatin into A and B compartments highlights regions of activity and inactivity, providing a window into the genomic activities specific to each cell type. Yet, the steep costs associated with acquiring Hi-C data, necessary for studying this compartmentalization across various cell types, pose a significant barrier in studying cell type specific genome organization. To address this, we present a prediction tool called compartment prediction using recurrent neural networks (CoRNN), which predicts compartmentalization of 3D genome using histone modification enrichment. CoRNN demonstrates robust cross-cell-type prediction of A/B compartments with an average AuROC of 90.9%. Cell-type-specific predictions align well with known functional elements, with H3K27ac and H3K36me3 identified as highly predictive histone marks. We further investigate our mispredictions and found that they are located in regions with ambiguous compartmental status. Furthermore, our model's generalizability is validated by predicting compartments in independent tissue samples, which underscores its broad applicability.
Sprache	Englisch
Erscheinungsdatum	2024-03-27
Erscheinungsland	United States
Dokumenttyp	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109570
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Biochemical and Cellular Assays to Assess the Effects of Acetylation on Base Excision Repair Enzymes.

Roychoudhury, Shrabasti / Pramanik, Suravi / Harris, Hannah L / Bhakat, Kishor K

Methods in molecular biology (Clifton, N.J.)

2019 Band 1983, Seite(n) 191–206

Abstract: Protein posttranslational modifications (PTMs), including acetylation, have emerged as important regulators for controlling many cellular processes. DNA base excision repair (BER), a highly coordinated multistep cellular process, is primarily involved in ...

Abstract	Protein posttranslational modifications (PTMs), including acetylation, have emerged as important regulators for controlling many cellular processes. DNA base excision repair (BER), a highly coordinated multistep cellular process, is primarily involved in the repair of both endogenous and drug-induced exogenous DNA base damages. BER relies on sequential recruitment and coordinated actions of multiple proteins. Increasing evidence suggests that acetylation of lysine residues of BER proteins facilitates fine-tuning of enzymatic activities, protein-protein interactions, and coordination of the steps in BER pathway. In this chapter, we describe detailed in vitro and in vivo approaches to examine the effect of acetylation on BER enzymes, focusing on the impact of acetylation of AP-endonuclease (APE1), a key enzyme in BER pathway, on its DNA damage repair activity, substrate-binding, and subcellular localization.
Mesh-Begriff(e)	Acetylation ; Biological Assay/methods ; Catalysis ; DNA Damage ; DNA Repair ; DNA Repair Enzymes/metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; Humans ; Protein Binding ; Recombinant Proteins ; Substrate Specificity
Chemische Substanzen	Recombinant Proteins ; APEX1 protein, human (EC 4.2.99.18) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18) ; DNA Repair Enzymes (EC 6.5.1.-)
Sprache	Englisch
Erscheinungsdatum	2019-05-13
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-9434-2_11
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: The human inactive X chromosome modulates expression of the active X chromosome.

Cell genomics

2023 Band 3, Heft 2, Seite(n) 100259

Abstract: The "inactive" X chromosome (Xi) has been assumed to have little impact, ... ...

Abstract	The "inactive" X chromosome (Xi) has been assumed to have little impact, in
Sprache	Englisch
Erscheinungsdatum	2023-02-08
Erscheinungsland	United States
Dokumenttyp	Journal Article
ISSN	2666-979X
ISSN (online)	2666-979X
DOI	10.1016/j.xgen.2023.100259
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome.

Roychoudhury, Shrabasti / Pramanik, Suravi / Harris, Hannah L / Tarpley, Mason / Sarkar, Aniruddha / Spagnol, Gaelle / Sorgen, Paul L / Chowdhury, Dipanjan / Band, Vimla / Klinkebiel, David / Bhakat, Kishor K

Proceedings of the National Academy of Sciences of the United States of America

2020 Band 117, Heft 21, Seite(n) 11409–11420

Abstract: Formation of G-quadruplex (G4) DNA structures in key regulatory regions in the genome has emerged as a secondary structure-based epigenetic mechanism for regulating multiple biological processes including transcription, replication, and telomere ... ...

Abstract	Formation of G-quadruplex (G4) DNA structures in key regulatory regions in the genome has emerged as a secondary structure-based epigenetic mechanism for regulating multiple biological processes including transcription, replication, and telomere maintenance. G4 formation (folding), stabilization, and unfolding must be regulated to coordinate G4-mediated biological functions; however, how cells regulate the spatiotemporal formation of G4 structures in the genome is largely unknown. Here, we demonstrate that endogenous oxidized guanine bases in G4 sequences and the subsequent activation of the base excision repair (BER) pathway drive the spatiotemporal formation of G4 structures in the genome. Genome-wide mapping of occurrence of Apurinic/apyrimidinic (AP) site damage, binding of BER proteins, and G4 structures revealed that oxidized base-derived AP site damage and binding of OGG1 and APE1 are predominant in G4 sequences. Loss of APE1 abrogated G4 structure formation in cells, which suggests an essential role of APE1 in regulating the formation of G4 structures in the genome. Binding of APE1 to G4 sequences promotes G4 folding, and acetylation of APE1, which enhances its residence time, stabilizes G4 structures in cells. APE1 subsequently facilitates transcription factor loading to the promoter, providing mechanistic insight into the role of APE1 in G4-mediated gene expression. Our study unravels a role of endogenous oxidized DNA bases and APE1 in controlling the formation of higher-order DNA secondary structures to regulate transcription beyond its well-established role in safeguarding the genomic integrity.
Mesh-Begriff(e)	A549 Cells ; Acetylation ; DNA Damage ; DNA Repair/physiology ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism ; G-Quadruplexes ; Gene Expression ; Genes, myc ; Genome, Human ; Guanine/chemistry ; Guanine/metabolism ; HCT116 Cells ; Humans ; Oxidation-Reduction ; Oxidative Stress/genetics ; Promoter Regions, Genetic ; Proto-Oncogene Proteins p21(ras)/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemische Substanzen	KRAS protein, human ; Transcription Factors ; Guanine (5Z93L87A1R) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; APEX1 protein, human (EC 4.2.99.18) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18)
Sprache	Englisch
Erscheinungsdatum	2020-05-13
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1912355117
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Chromatin alternates between A and B compartments at kilobase scale for subgenic organization.

Harris, Hannah L / Gu, Huiya / Olshansky, Moshe / Wang, Ailun / Farabella, Irene / Eliaz, Yossi / Kalluchi, Achyuth / Krishna, Akshay / Jacobs, Mozes / Cauer, Gesine / Pham, Melanie / Rao, Suhas S P / Dudchenko, Olga / Omer, Arina / Mohajeri, Kiana / Kim, Sungjae / Nichols, Michael H / Davis, Eric S / Gkountaroulis, Dimos /

Udupa, Devika / Aiden, Aviva Presser / Corces, Victor G / Phanstiel, Douglas H / Noble, William Stafford / Nir, Guy / Di Pierro, Michele / Seo, Jeong-Sun / Talkowski, Michael E / Aiden, Erez Lieberman / Rowley, M Jordan

Nature communications

2023 Band 14, Heft 1, Seite(n) 3303

Abstract: Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal ... ...

Abstract	Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling. Producing a large Hi-C map with 33 billion contacts in conjunction with an algorithm for performing principal component analysis on sparse, super massive matrices (POSSUMM), we resolve compartments to 500 bp. Our results demonstrate that essentially all active promoters and distal enhancers localize in the A compartment, even when flanking sequences do not. Furthermore, we find that the TSS and TTS of paused genes are often segregated into separate compartments. We then identify diffuse interactions that radiate from CTCF loop anchors, which correlate with strong enhancer-promoter interactions and proximal transcription. We also find that these diffuse interactions depend on CTCF's RNA binding domains. In this work, we demonstrate features of fine-scale chromatin organization consistent with a revised model in which compartments are more precise than commonly thought while CTCF loops are more protracted.
Mesh-Begriff(e)	Chromatin/genetics ; CCCTC-Binding Factor/genetics ; CCCTC-Binding Factor/metabolism ; Enhancer Elements, Genetic/genetics ; Cell Nucleus/genetics ; Cell Nucleus/metabolism ; Promoter Regions, Genetic
Chemische Substanzen	Chromatin ; CCCTC-Binding Factor
Sprache	Englisch
Erscheinungsdatum	2023-06-06
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38429-1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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