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The AaFoxA factor regulates female reproduction through chromatin remodeling in the mosquito vector Aedes aegypti.

Female mosquitoes are vectors of many devastating human diseases because they require blood feeding to initiate reproduction. Thus, elucidation of molecular mechanisms managing female mosquito reproduction is essential. Although the regulation of gene expression during the mosquito gonadotrophic cycle has been studied in detail, how this process is controlled at the chromatin level remains unclear. Chromatin must be accessible for transcription factors (TFs) governing gene expression. A specialized class of TFs, called pioneer factors (PFs), binds and remodels closed chromatin, permitting othe…

Genetically regulated eRNA expression predicts chromatin contact frequency and reveals genetic mechanisms at GWAS loci.

The biological functions of extragenic enhancer RNAs and their impact on disease risk remain relatively underexplored. In this work, we develop in silico models of genetically regulated expression of enhancer RNAs across 49 cell and tissue types, characterizing their degree of genetic control. Leveraging the estimated genetically regulated expression for enhancer RNAs and canonical genes in a large-scale DNA biobank (N > 70,000) and high-resolution Hi-C contact data, we train a deep learning-based model of pairwise three-dimensional chromatin contact frequency for enhancer-enhancer and enhance…

Protocol for analyzing chromatin dynamics in macrophage-internalized Candida glabrata cells using micrococcal nuclease digestion.

Chromatin dynamics plays an important role in medical mycology. Here, we present a protocol to identify nucleosome occupancy and positioning in the fungal pathogen Candida glabrata (Nakaseomyces glabratus). This process involves micrococcal nuclease (MNase) digestion of the chromatin of C. glabrata cells (grown in RPMI medium or inside macrophages), followed by the purification of mononucleosomal DNA fragments. We describe steps for standardizing MNase digestion and identifying genome-wide dynamic nucleosomes using a next-generation sequencing approach. For complete details on the use and exec…

Chromatin changes associated with neutrophil extracellular trap formation in whole blood reflect complex immune signaling.

BACKGROUND: Neutrophils are key players in innate immunity, forming neutrophil extracellular traps (NETs) to defend against infections. However, excess NET formation is implicated in inflammatory conditions such as sepsis and immunothrombosis. Studying NET formation in isolated neutrophils provides important mechanistic insights but does not reflect the complexity of immune interactions in whole blood, limiting our understanding of neutrophil responses. METHODS: This study investigates chromatin accessibility changes using Assay for Transposase-Accessible Chromatin with sequencing (ATAC-Seq) …

Chromatin remodeler BRD9 represses transcription of PPARα target genes, including CPT1A to suppress lipid metabolism.

Peroxisome proliferator-activated receptor α (PPARα) regulates the transcription of fatty acid oxidation-related genes, such as carnitine palmitoyltransferase 1A (CPT1A), to maintain lipid homeostasis. Recent studies have suggested the involvement of switch/sucrose non-fermentable (SWI/SNF) complexes in nuclear receptor-mediated transcription. SWI/SNF complexes are chromatin remodeling factors classified into three complexes: canonical brahma-related gene 1-/brahma-associated factor (cBAF), polybromo BAF (PBAF), and non-canonical BAF (ncBAF). Among these, the key regulator of PPARα-mediated tr…

Hierarchical Prediction and Perturbation of Chromatin Organization Reveal How Loop Domains Mediate Higher-Order Architectures.

The genome is folded within the dense cell nucleus in a hierarchical manner, resulting in complex interactions between distinct folding strategies at various length scales. To elucidate how short-range loop domains regulate higher-order structures of the chromatin, such as topologically associating domains (TADs) and compartments, HiCGen is introduced as a hierarchical and cell-type-specific generator based on Swin-transformer architecture. HiCGen predicts genome organization across different spatial scales utilizing DNA sequence and genomic features as inputs. The model enables in silico scre…

IFI16 Mediates Deacetylation of KSHV Chromatin via Interaction with NuRD and Sin3A Co-Repressor Complexes.

IFI16 is a well-characterized nuclear innate immune DNA sensor that detects foreign dsDNA, including herpesviral genomes, to activate the in … ed whether these IFI16-HDAC1/2 interactions contribute to broader epigenetic regulation of the KSHV chromatin. Our findings reveal that IFI16 associates with and facilitates the recruitment of the NuRD and Sin3A co-repressor complexes-both multiprotein, HDAC1/2-containing chromatin regulators-on KSHV episomes. Depletion of IFI16 led to reductions in NuRD an …

Sperm chromatin dispersion assay reliability and assisted reproductive technology outcomes: Systematic review and meta-analysis.

OBJECTIVE: Elevated sperm DNA fragmentation has potential implications for semen quality and fertility. The commonly used sperm chromatin dispersion test offers an indirect estimation but has limitations in terms of bias and variability. This study aimed to assess the reliability of the sperm chromatin dispersion assay for predicting assisted reproductive technology outcomes. MATERIALS AND METHODS: This systematic review included studies published until December 2023 that adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed/MEDLINE, Scopus, and …

PRDM3/16 regulate chromatin accessibility required for NKX2-1 mediated alveolar epithelial differentiation and function.

While the critical role of NKX2-1 and its transcriptional targets in lung morphogenesis and pulmonary epithelial cell differentiation is increasingly known, mechanisms by which chromatin accessibility alters the epigenetic landscape and how NKX2-1 interacts with other co-activators required for alveolar epithelial cell differentiation and function are not well understood. Combined deletion of the histone methyl transferases Prdm3 and Prdm16 in early lung endoderm causes perinatal lethality due to respiratory failure from loss of AT2 cells and the accumulation of partially differentiated AT1 ce…

DeCOOC Deconvoluted Hi-C Map Characterizes the Chromatin Architecture of Cells in Physiologically Distinctive Tissues.

Deciphering variations in chromosome conformations based on bulk three-dimensional (3D) genomic data from heterogenous tissues is a key to understanding cell-type specific genome architecture and dynamics. Surprisingly, computational deconvolution methods for high-throughput chromosome conformation capture (Hi-C) data remain very rare in the literature. Here, a deep convolutional neural network (CNN), deconvolve bulk Hi-C data (deCOOC) that remarkably outperformed all the state-of-the-art tools in the deconvolution task is developed. Interestingly, it is noticed that the chromatin accessibilit…

XPC-PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair.

Cells employ global genome nucleotide excision repair (GGR) to eliminate a broad spectrum of DNA lesions, including those induced by UV light. The lesion-recognition factor XPC initiates repair of helix-destabilizing DNA lesions, but binds poorly to lesions such as CPDs that do not destabilize DNA. How difficult-to-repair lesions are detected in chromatin is unknown. Here, we identify the poly-(ADP-ribose) polymerases PARP1 and PARP2 as constitutive interactors of XPC. Their interaction results in the XPC-stimulated synthesis of poly-(ADP-ribose) (PAR) by PARP1 at UV lesions, which in turn ena…

The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived …

Evaluation of sperm chromatin/DNA integrity, morphology, and Catsper expression on diabetic C57BL/6 mice.

BACKGROUND: Diabetes is associated with reproductive impairment on the male reproductive system and causes complications such as decreased l … unohistochemical, TUNEL studies, and biochemical assay. RESULTS: Results of this study showed that chromatin integrity, morphology, cation channels of sperm (Catsper) expression, and biochemical factors level were significantly changed in diabetic mice in comparison to other groups (P<0.05) and treatment with insulin improved these parameters. CONCLUSION: …

Interrogating Global Chromatin Interaction Network by High-Throughput Chromosome Conformation Capture (Hi-C) in Plants.

High-throughput chromosome conformation capture (Hi-C) enables the global quantification of chromatin interaction frequency in eukaryotic nuclei. This method is based on in situ Hi-C, in which chromatin is cross-linked with formaldehyde, then digested with restriction enzyme. Biotin-labeled nucleotide is incorporated before the spatially adjacent DNA ends are ligated, making it possible to enrich specifically the chimeric ligation products for deep sequencing. In this chapter, we describe a modified in situ Hi-C protocol for the global chromatin interaction analysis in plants.

Arctic introgression and chromatin regulation facilitated rapid Qinghai-Tibet Plateau colonization by an avian predator.

The Qinghai-Tibet Plateau (QTP), possesses a climate as cold as that of the Arctic, and also presents uniquely low oxygen concentrations and intense ultraviolet (UV) radiation. QTP animals have adapted to these extreme conditions, but whether they obtained genetic variations from the Arctic during cold adaptation, and how genomic mutations in non-coding regions regulate gene expression under hypoxia and intense UV environment, remain largely unknown. Here, we assemble a high-quality saker falcon genome and resequence populations across Eurasia. We identify female-biased hybridization with Arct

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation.

To investigate the three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia and mantle cell lymphoma patients, here we integrate in situ Hi-C and nine additional omics layers. Beyond conventional active (A) and inactive (B) compartments, we uncover a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, 28% of the compartments change, mostly involving a widespread chromatin activation from naive to germinal center B cells and a…

Early-life midazolam exposure persistently changes chromatin accessibility to impair adult hippocampal neurogenesis and cognition.

Linkage between early-life exposure to anesthesia and subsequent learning disabilities is of great concern to children and their families. Here we show that early-life exposure to midazolam (MDZ), a widely used drug in pediatric anesthesia, persistently alters chromatin accessibility and the expression of quiescence-associated genes in neural stem cells (NSCs) in the mouse hippocampus. The alterations led to a sustained restriction of NSC proliferation toward adulthood, resulting in a reduction of neurogenesis that was associated with the impairment of hippocampal-dependent memory functions. M…

Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma.

Myeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of foca

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… We further confirmed the functional association of CREB and MMSET on the DKK1 promoter using a chromatin immunoprecipitation (ChIP) assay. … For ChIP-qPCR assay, chromatin samples were immunoprecipitated with antibodies against CREB, MMSET, H3K36me2, or control IgG at 4 °C overnight, and immunoprecipitates or total chromatin input were isolated and analyzed by real-time PCR with primers specific for the promoter regions of DKK1 gene (Supplementary …

Persistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling.

Self-reactive CD8+ T cells are important mediators of progressive tissue damage in autoimmune diseases, but the molecular program underlying these cells' functional adaptation is unclear. Here we characterize the transcriptional and epigenetic landscape of self-reactive CD8+ T cells in a mouse model of protracted central nervous system (CNS) autoimmunity and compare it to populations of CNS-resident memory CD8+ T cells emerging from acute viral infection. We find that autoimmune CD8+ T cells persisting at sites of self-antigen exhibit characteristic transcriptional regulation together with dis

Epigenetic reprogramming and chromatin accessibility in pediatric diffuse intrinsic pontine gliomas: a neural developmental disease.

Diffuse intrinsic pontine glioma (DIPG) is a rare but deadly pediatric brainstem tumor. To date, there is no effective therapy for DIPG. Transcriptomic analyses have revealed DIPGs have a distinct profile from other pediatric high-grade gliomas occurring in the cerebral hemispheres. These unique genomic characteristics coupled with the younger median age group suggest that DIPG has a developmental origin. The most frequent mutation in DIPG is a lysine to methionine (K27M) mutation that occurs on H3F3A and HIST1H3B/C, genes encoding histone variants. The K27M mutation disrupts methylation by po