Synthesis and Application of Cell-Permeable Metabolites for Modulating Chromatin Modifications Regulated by α-Ketoglutarate-Dependent Enzymes

AbstractAlternative splicing relies on the combinatorial recruitment of splicing regulators to specific RNA binding sites. Chromatin has been shown to impact this recruitment. However, a limited number of histone marks have been studied at a global level. In this work, a machine learning approach, applied to extensive epigenomics datasets in human H1 embryonic stem cells and IMR90 foetal fibroblasts, has identified eleven chromatin modifications that differentially mark alternatively spliced exons depending on the level of exon inclusion. These marks act in a combinatorial and position-dependent way, creating characteristic splicing-associated chromatin signatures (SACS). In support of a functional role for SACS in coordinating splicing regulation, changes in the alternative splicing of SACS-marked exons between ten different cell lines correlate with changes in SACS enrichment levels and recruitment of the splicing regulators predicted by RNA motif search analysis. We propose the dynamic nature of chromatin modifications as a mechanism to rapidly fine-tune alternative splicing when necessary.

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Cellular macromolecules-tethered DNA walking indexing to explore nanoenvironments of chromatin modifications

Nature Communications ◽

10.1038/s41467-021-22284-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Feng Chen ◽

Min Bai ◽

Xiaowen Cao ◽

Jing Xue ◽

Yue Zhao ◽

...

Keyword(s):

Fluorescence Imaging ◽

Spatial Organization ◽

High Throughput Sequencing ◽

Dna Amplification ◽

Chromatin Modifications ◽

Dynamic Changes ◽

Recognition Mechanism ◽

Cell Cycles ◽

Dna Modifications ◽

Relationship Of

AbstractExploring spatial organization and relationship of diverse biomolecules within cellular nanoenvironments is important to elucidate the fundamental processes of life. However, it remains methodologically challenging. Herein, we report a molecular recognition mechanism cellular macromolecules-tethered DNA walking indexing (Cell-TALKING) to probe the nanoenvironments containing diverse chromatin modifications. As an example, we characterize the nanoenvironments of three DNA modifications around one histone posttranslational modification (PTM). These DNA modifications in fixed cells are labeled with respective DNA barcoding probes, and then the PTM site is tethered with a DNA walking probe. Cell-TALKING can continuously produce cleavage records of any barcoding probes nearby the walking probe. New 3’-OH ends are generated on the cleaved barcoding probes to induce DNA amplification for downstream detections. Combining fluorescence imaging, we identify various combinatorial chromatin modifications and investigate their dynamic changes during cell cycles. We also explore the nanoenvironments in different cancer cell lines and clinical specimens. In principle, using high-throughput sequencing instead of fluorescence imaging may allow the detection of complex cellular nanoenvironments containing tens of biomolecules such as transcription factors.

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DNMT1 reads heterochromatic H4K20me3 to reinforce LINE-1 DNA methylation

Nature Communications ◽

10.1038/s41467-021-22665-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Wendan Ren ◽

Huitao Fan ◽

Sara A. Grimm ◽

Jae Jin Kim ◽

Linhui Li ◽

...

Keyword(s):

Dna Methylation ◽

Dna Methyltransferase ◽

Histone H3 ◽

Genomic Stability ◽

Mammalian Genome ◽

Dna Methyltransferase 1 ◽

Chromatin Modifications ◽

Direct Link ◽

Histone H4 ◽

Radiation Induced

AbstractDNA methylation and trimethylated histone H4 Lysine 20 (H4K20me3) constitute two important heterochromatin-enriched marks that frequently cooperate in silencing repetitive elements of the mammalian genome. However, it remains elusive how these two chromatin modifications crosstalk. Here, we report that DNA methyltransferase 1 (DNMT1) specifically ‘recognizes’ H4K20me3 via its first bromo-adjacent-homology domain (DNMT1BAH1). Engagement of DNMT1BAH1-H4K20me3 ensures heterochromatin targeting of DNMT1 and DNA methylation at LINE-1 retrotransposons, and cooperates with the previously reported readout of histone H3 tail modifications (i.e., H3K9me3 and H3 ubiquitylation) by the RFTS domain to allosterically regulate DNMT1’s activity. Interplay between RFTS and BAH1 domains of DNMT1 profoundly impacts DNA methylation at both global and focal levels and genomic resistance to radiation-induced damage. Together, our study establishes a direct link between H4K20me3 and DNA methylation, providing a mechanism in which multivalent recognition of repressive histone modifications by DNMT1 ensures appropriate DNA methylation patterning and genomic stability.

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Stiffness and Aging in Cardiovascular Diseases: The Dangerous Relationship between Force and Senescence

International Journal of Molecular Sciences ◽

10.3390/ijms22073404 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3404

Author(s):

Silvia Ferrari ◽

Maurizio Pesce

Keyword(s):

Risk Factors ◽

Aging Process ◽

Tissue Structure ◽

Biological Aging ◽

Ros Production ◽

Oxygen Species ◽

Chromatin Modifications ◽

Gradual Decline ◽

Cycle Arrest ◽

Inflammatory Activation

Biological aging is a process associated with a gradual decline in tissues’ homeostasis based on the progressive inability of the cells to self-renew. Cellular senescence is one of the hallmarks of the aging process, characterized by an irreversible cell cycle arrest due to reactive oxygen species (ROS) production, telomeres shortening, chronic inflammatory activation, and chromatin modifications. In this review, we will describe the effects of senescence on tissue structure, extracellular matrix (ECM) organization, and nucleus architecture, and see how these changes affect (are affected by) mechano-transduction. In our view, this is essential for a deeper understanding of the progressive pathological evolution of the cardiovascular system and its relationship with the detrimental effects of risk factors, known to act at an epigenetic level.

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