The Nuclear Lamina as an Organizer of Chromosome Architecture

The nuclear lamina (NL) is a meshwork of lamins and lamin-associated proteins adjoining the inner side of the nuclear envelope. In early embryonic cells, the NL mainly suppresses background transcription, whereas, in differentiated cell types, its disruption affects gene expression more severely. Normally, the NL serves as a backbone for multiple chromatin anchoring sites, thus shaping the spatial organization of chromosomes in the interphase nucleus. However, upon cell senescence, aging, or in some types of terminally differentiated cells and lamin-associated diseases, the loss of NL-chromatin tethering causes drastic alterations in chromosome architecture. Here, we provide an overview of the recent advances in the field of NL-chromatin interactions, focusing on their impact on chromatin positioning, compaction, repression, and spatial organization.

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Large organized chromatin lysine domains help distinguish primitive from differentiated cell populations

Nature Communications ◽

10.1038/s41467-020-20830-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Seyed Ali Madani Tonekaboni ◽

Benjamin Haibe-Kains ◽

Mathieu Lupien

Keyword(s):

Transposable Elements ◽

Histone Modifications ◽

Cell Types ◽

Regulatory Elements ◽

Cell Populations ◽

Genomic Features ◽

Differentiated Cells ◽

Chromatin Interactions ◽

Topologically Associating Domains ◽

Highly Expressed Genes

AbstractThe human genome is partitioned into a collection of genomic features, inclusive of genes, transposable elements, lamina interacting regions, early replicating control elements and cis-regulatory elements, such as promoters, enhancers, and anchors of chromatin interactions. Uneven distribution of these features within chromosomes gives rise to clusters, such as topologically associating domains (TADs), lamina-associated domains, clusters of cis-regulatory elements or large organized chromatin lysine (K) domains (LOCKs). Here we show that LOCKs from diverse histone modifications discriminate primitive from differentiated cell types. Active LOCKs (H3K4me1, H3K4me3 and H3K27ac) cover a higher fraction of the genome in primitive compared to differentiated cell types while repressive LOCKs (H3K9me3, H3K27me3 and H3K36me3) do not. Active LOCKs in differentiated cells lie proximal to highly expressed genes while active LOCKs in primitive cells tend to be bivalent. Genes proximal to bivalent LOCKs are minimally expressed in primitive cells. Furthermore, bivalent LOCKs populate TAD boundaries and are preferentially bound by regulators of chromatin interactions, including CTCF, RAD21 and ZNF143. Together, our results argue that LOCKs discriminate primitive from differentiated cell populations.

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The Toolbox for Untangling Chromosome Architecture in Immune Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.670884 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shuai Liu ◽

Keji Zhao

Keyword(s):

Gene Expression ◽

Immune Cells ◽

Spatial Organization ◽

Chromosome Structure ◽

Immune Cell ◽

Genome Structure ◽

Chromosome Architecture ◽

The Past ◽

Important Player ◽

The Way

The code of life is not only encrypted in the sequence of DNA but also in the way it is organized into chromosomes. Chromosome architecture is gradually being recognized as an important player in regulating cell activities (e.g., controlling spatiotemporal gene expression). In the past decade, the toolbox for elucidating genome structure has been expanding, providing an opportunity to explore this under charted territory. In this review, we will introduce the recent advancements in approaches for mapping spatial organization of the genome, emphasizing applications of these techniques to immune cells, and trying to bridge chromosome structure with immune cell activities.

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Phosphorylation-dependent mitotic SUMOylation drives nuclear envelope–chromatin interactions

The Journal of Cell Biology ◽

10.1083/jcb.202103036 ◽

2021 ◽

Vol 220 (12) ◽

Cited By ~ 1

Author(s):

Christopher Ptak ◽

Natasha O. Saik ◽

Ashwini Premashankar ◽

Diego L. Lapetina ◽

John D. Aitchison ◽

...

Keyword(s):

Gene Expression ◽

Nuclear Envelope ◽

Spatial Organization ◽

G1 Phase ◽

Nuclear Pore ◽

Nuclear Pore Complexes ◽

Chromatin Binding ◽

Chromatin Interactions ◽

Sumo Ligase ◽

Pore Complexes

In eukaryotes, chromatin binding to the inner nuclear membrane (INM) and nuclear pore complexes (NPCs) contributes to spatial organization of the genome and epigenetic programs important for gene expression. In mitosis, chromatin–nuclear envelope (NE) interactions are lost and then formed again as sister chromosomes segregate to postmitotic nuclei. Investigating these processes in S. cerevisiae, we identified temporally and spatially controlled phosphorylation-dependent SUMOylation events that positively regulate postmetaphase chromatin association with the NE. Our work establishes a phosphorylation-mediated targeting mechanism of the SUMO ligase Siz2 to the INM during mitosis, where Siz2 binds to and SUMOylates the VAP protein Scs2. The recruitment of Siz2 through Scs2 is further responsible for a wave of SUMOylation along the INM that supports the assembly and anchorage of subtelomeric chromatin at the INM and localization of an active gene (INO1) to NPCs during the later stages of mitosis and into G1-phase.

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Enhancer-dependence of gene expression increases with developmental age

10.1101/678334 ◽

2019 ◽

Author(s):

Wenqing Cai ◽

Jialiang Huang ◽

Qian Zhu ◽

Bin E. Li ◽

Davide Seruggia ◽

...

Keyword(s):

Gene Expression ◽

Developmental Stages ◽

Chromatin Accessibility ◽

List Type ◽

Primary Cells ◽

Embryonic Cells ◽

Human Origin ◽

Chromatin Interactions ◽

Developmental Age ◽

Specific Control

SummaryHow overall principles of gene regulation (the “logic”) may change during ontogeny is largely unexplored. We compared transcriptomic, epigenomic and topological profiles in embryonic (EryP) and adult (EryD) erythroblasts. Despite reduced chromatin accessibility compared to EryP, distal chromatin of EryD is enriched in H3K27ac, Gata1 and Myb occupancy. In contrast to EryP-specific genes, which exhibit promoter-centric regulation through Gata1, EryD-specific genes employ distal enhancers for long-range regulation through enhancer-promoter looping, confirmed by Gata1 HiChIP. Genome editing demonstrated distal enhancers are required for gene expression in EryD but not in EryP. Applying a metric for enhancer-dependence of transcription, we observed a progressive reliance on enhancer control with increasing age of ontogeny among diverse primary cells and tissues of mouse and human origin. Our findings highlight fundamental and conserved differences in regulatory logic at distinct developmental stages, characterized by simpler promoter-centric regulation in embryonic cells and combinatorial enhancer-driven control in adult cells.HighlightsRegulation of embryonic-specific erythroid genes is promoter-centric through Gata1Adult-specific control is combinatorial enhancer-driven and requires MybAdult specific genes have increased enhancer-promoter chromatin interactionsEnhancer-dependence increases progressively with increasing developmental age

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MUNIn (Multiple cell-type UNifying long-range chromatin Interaction detector): a statistical framework for identifying long-range chromatin interactions from multiple cell types

10.1101/2020.11.12.380782 ◽

2020 ◽

Author(s):

Weifang Liu ◽

Armen Abnousi ◽

Qian Zhang ◽

Yun Li ◽

Ming Hu ◽

...

Keyword(s):

Long Range ◽

Spatial Organization ◽

Critical Role ◽

Cell Types ◽

Chromatin Interaction ◽

Cell Type ◽

Statistical Framework ◽

Chromatin Interactions ◽

The Status ◽

Multiple Cell

AbstractChromatin spatial organization (interactome) plays a critical role in genome function. Deep understanding of chromatin interactome can shed insights into transcriptional regulation mechanisms and human disease pathology. One essential task in the analysis of chromatin interactomic data is to identify long-range chromatin interactions. Existing approaches, such as HiCCUPS, FitHiC/FitHiC2 and FastHiC, are all designed for analyzing individual cell types. None of them accounts for unbalanced sequencing depths and heterogeneity among multiple cell types in a unified statistical framework. To fill in the gap, we have developed a novel statistical framework MUNIn (Multiple cell-type UNifying long-range chromatin Interaction detector) for identifying long-range chromatin interactions from multiple cell types. MUNIn adopts a hierarchical hidden Markov random field (H-HMRF) model, in which the status (peak or background) of each interacting chromatin loci pair depends not only on the status of loci pairs in its neighborhood region, but also on the status of the same loci pair in other cell types. To benchmark the performance of MUNIn, we performed comprehensive simulation studies and real data analysis, and showed that MUNIn can achieve much lower false positive rates for detecting cell-type-specific interactions (33.1 - 36.2%), and much enhanced statistical power for detecting shared peaks (up to 74.3%), compared to uni-cell-type analysis. Our data demonstrated that MUNIn is a useful tool for the integrative analysis of interactomic data from multiple cell types.

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Local translation in synaptic mitochondria influences synaptic transmission

10.1101/2020.07.22.215194 ◽

2020 ◽

Author(s):

Roya Yousefi ◽

Eugenio F. Fornasiero ◽

Lukas Cyganek ◽

Stefan Jakobs ◽

Silvio O. Rizzoli ◽

...

Keyword(s):

Gene Expression ◽

Hippocampal Neurons ◽

Spatial Organization ◽

Mitochondrial Gene ◽

Cell Types ◽

Synaptic Function ◽

Synaptic Activity ◽

Mitochondrial Gene Expression ◽

Mitochondrial Translation ◽

Ample Evidence

ABSTRACTMitochondria possess a small genome that codes for core subunits of the oxidative phosphorylation system, and whose expression is essential for energy production. Information on the regulation and spatial organization of mitochondrial gene expression in the cellular context has been difficult to obtain. Here we addressed this by devising an imaging approach to analyze mitochondrial translation, by following the incorporation of clickable non-canonical amino acids. We applied this method to multiple cell types, including hippocampal neurons, where we found ample evidence for mitochondrial translation in both dendrites and axons. Translation levels were surprisingly heterogeneous, were typically stronger in axons, and were independent of their distance from the cell soma, where mitochondria presumably descent from. Presynaptic mitochondrial translation correlated with local synaptic activity, and blocking mitochondria translation reduced synaptic function. Overall, these findings demonstrate that mitochondrial gene expression in neurons is intimately linked to neuronal function.

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CT-FOCS: a novel method for inferring cell type-specific enhancer-promoter maps

10.1101/707158 ◽

2019 ◽

Author(s):

Tom Aharon Hait ◽

Ran Elkon ◽

Ron Shamir

Keyword(s):

Gene Expression ◽

Target Genes ◽

Expression Patterns ◽

Cell Types ◽

Specific Gene ◽

Cell Type ◽

Chromatin Interactions ◽

Cell Type Specific ◽

Novel Method ◽

Validation Scheme

AbstractSpatiotemporal gene expression patterns are governed to a large extent by enhancer elements, typically located distally from their target genes. Identification of enhancer-promoter (EP) links that are specific and functional in individual cell types is a key challenge in understanding gene regulation. We introduce CT-FOCS, a new statistical inference method that utilizes multiple replicates per cell type to infer cell type-specific EP links. Computationally predicted EP links are usually benchmarked against experimentally determined chromatin interactions measured by ChIA-PET and promoter-capture HiC techniques. We expand this validation scheme by using also loops that overlap in their anchor sites. In analyzing 1,366 samples from ENCODE, Roadmap epigenomics and FANTOM5, CT-FOCS inferred highly cell type-specific EP links more accurately than state-of-the-art methods. We illustrate how our inferred EP links drive cell type-specific gene expression and regulation.

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Nuclear Pore Complex Acetylation Regulates mRNA Export and Cell Cycle Commitment in Budding Yeast

10.1101/2021.09.01.458533 ◽

2021 ◽

Author(s):

Mercè Gomar-Alba ◽

Vasilisa Pozharskaia ◽

Celia Schaal ◽

Arun Kumar ◽

Basile Jacquel ◽

...

Keyword(s):

Gene Expression ◽

Nuclear Export ◽

Mrna Export ◽

Cell Types ◽

Nuclear Pore ◽

Specific Cell ◽

Nuclear Pore Complexes ◽

Daughter Cells ◽

Associated Proteins ◽

Pore Complexes

AbstractNuclear pore complexes (NPCs) mediate communication between the nucleus and the cytoplasm and regulate gene expression by interacting with transcription and mRNA export factors. Lysine acetyl-transferases (KATs) promote transcription through acetylation of chromatin-associated proteins. We find that Esa1, the KAT subunit of the yeast NuA4 complex, also acetylates the nuclear pore basket component Nup60 to promote mRNA export. Acetylation of Nup60 recruits mRNA export factors to the nuclear basket, including the scaffolding subunit of the Transcription and Export 2 (TREX-2) complex, Sac3. Esa1-dependent nuclear export of mRNAs promotes entry into S phase, and is inhibited by the Hos3 deacetylase in G1 daughter cells to restrain their premature commitment to a new cell division cycle. This mechanism also inhibits expression of the nutrient-regulated GAL1 gene specifically in daughter cells. These results reveal how acetylation contributes to the functional plasticity of NPCs in specific cell types, and demonstrate how the evolutionarily conserved NuA4 complex regulates gene expression dually at the level of transcription and mRNA export, by modifying the nucleoplasmic entrance to nuclear pores.

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TET-catalyzed 5-hydroxymethylcytosine regulates gene expression in differentiating colonocytes and colon cancer

Scientific Reports ◽

10.1038/srep17568 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 39

Author(s):

Christopher G. Chapman ◽

Christopher J. Mariani ◽

Feng Wu ◽

Katherine Meckel ◽

Fatma Butun ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Regulation Of Gene Expression ◽

Human Colon ◽

Cell Types ◽

Enzymatic Oxidation ◽

Dna Hydroxymethylation ◽

Differentiated Cells ◽

Colon Cancers

Abstract The formation of differentiated cell types from pluripotent progenitors involves epigenetic regulation of gene expression. DNA hydroxymethylation results from the enzymatic oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) 5-mC dioxygenase enzymes. Previous work has mapped changes in 5-mC during differentiation of intestinal stem cells. However, whether or not 5-hmC regulates colonocyte differentiation is unknown. Here we show that 5-hmC regulates gene expression during colonocyte differentiation and controls gene expression in human colon cancers. Genome-wide profiling of 5-hmC during in vitro colonic differentiation demonstrated that 5-hmC is gained at highly expressed and induced genes and is associated with intestinal transcription factor binding sites, including those for HNF4A and CDX2. TET1 induction occurred during differentiation and TET1 knockdown altered gene expression and inhibited barrier formation of colonocytes. We find that the 5-hmC distribution in primary human colonocytes parallels the distribution found in differentiated cells in vitro and that gene-specific 5-hmC changes in human colon cancers are directly correlated with changes in gene expression. Our results support a model in which 5-hmC regulates differentiation of adult human intestine and 5-hmC alterations contribute to the disrupted gene expression in colon cancer.

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Differentiation of trophoblast cells from human embryonic stem cells: to be or not to be?

Reproduction ◽

10.1530/rep-14-0080 ◽

2014 ◽

Vol 147 (5) ◽

pp. D1-D12 ◽

Cited By ~ 35

Author(s):

R Michael Roberts ◽

Kyle M Loh ◽

Mitsuyoshi Amita ◽

Andreia S Bernardo ◽

Katsuyuki Adachi ◽

...

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Full Range ◽

Embryonic Stem ◽

Cell Types ◽

Embryonic Cells ◽

Cell Type ◽

Differentiated Cells ◽

Developmental Hierarchy

It is imperative to unveil the full range of differentiated cell types into which human pluripotent stem cells (hPSCs) can develop. The need is twofold: it will delimit the therapeutic utility of these stem cells and is necessary to place their position accurately in the developmental hierarchy of lineage potential. Accumulated evidence suggested that hPSC could develop in vitro into an extraembryonic lineage (trophoblast (TB)) that is typically inaccessible to pluripotent embryonic cells during embryogenesis. However, whether these differentiated cells are truly authentic TB has been challenged. In this debate, we present a case for and a case against TB differentiation from hPSCs. By analogy to other differentiation systems, our debate is broadly applicable, as it articulates higher and more challenging standards for judging whether a given cell type has been genuinely produced from hPSC differentiation.

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