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PubMed2025

iNOME-seq: in vivo simultaneous genome-wide mapping of chromatin accessibility, nucleosome positioning, DNA-binding protein sites, and DNA methylation in Arabidopsis.

We present iNOMe-seq, a novel method for in vivo simultaneous profiling of chromatin accessibility, nucleosome occupancy, DNA-binding protein sites, and DNA methylation in living tissues. iNOMe-seq utilizes an m5C methyltransferase to mark accessible cytosines in a GpC context, bypassing nucleosome-restricted regions. Using Arabidopsis thaliana, we demonstrate that iNOMe-seq improves chromatin accessibility quantification compared to existing methods. Furthermore, it allows for the spatial and temporal analysis of chromatin dynamics, transcription factor binding, and DNA methylation, offering insight into the role of epigenetic components in transcriptional regulation across tissues and genetic variations in natural populations.

Arabidopsis↗
PubMed2025

E2F1 induces a G0-G1 reentry transcriptional program without changing chromatin accessibility.

Quiescent cells actively repress cell-cycle genes via chromatin-based mechanisms to maintain a non-dividing state, yet remain poised to reenter upon stimulation. E2F1, a canonical activator of cell-cycle genes, is sufficient to induce reentry from quiescence, but how it overcomes chromatin-mediated repression remains unclear. Here, we show that inducible E2F1 expression triggers exit from quiescence and progression through the cycle without changes in chromatin accessibility, by harnessing regulatory elements with limited, pre-existing accessibility. Using time-resolved transcriptomics, we demonstrate that E2F1 induces an accelerated transcriptional program compared to serum. Unlike serum, which triggers broad chromatin remodeling, E2F1-induced activation occurs in a context of limited accessibility. ChIP-seq reveals that E2F1 directly binds target sites in quiescent cells to upregulate canonical genes. Biochemical reconstitution shows that E2F1 binds nucleosomes and accesses internal E2F sites within histone-wrapped DNA. These findings suggest that E2F1 can engage nucleosome-associated DNA and initiate transcription without major chromatin reorganization, redefining transcription factor-chromatin dynamics during cell fate transitions and establishing E2F1 as a potent regulator of cell-cycle reentry.

Journal Article↗
PubMed2026

Refining sequence-to-expression modelling with chromatin accessibility.

MOTIVATION: Sequence-to-expression models typically do not consider chromatin accessibility, a major factor limiting gene regulation. We hypothesized that supplying accessibility as an input feature would allow a sequence-to-expression model to focus on important open regions of the genome. RESULTS: We found that the performance of such an augmented model was significantly better than that of sequence-only or accessibility-only models with similar architectures. Specifically, its ability to predict the expression of highly variable genes and gene expression in other cell types improved, and higher attribution scores in the input DNA sequences of the augmented model conformed to accessibility, enabling the learning of cell type-specific sequence patterns. Additionally, we show that fine-tuning a pre-trained sequence-only model with both sequence and accessibility can boost performance further and highlight the importance of sequencing depth in sequence-to-expression prediction. AVAILABILITY AND IMPLEMENTATION: Source code is available on GitHub at https://github.com/lapohosorsolya/accessible_seq2exp.

Chromatin↗
PubMed2026

Nucleolin promotes neuropathic pain by increasing chromatin accessibility at the Ccl2 promoter in primary sensory neurons.

Nerve injury-induced transcriptional alterations in primary sensory neurons of the dorsal root ganglion (DRG) constitute a key molecular basis for the development of neuropathic pain. Nucleolin (NCL), a highly conserved multifunctional nucleolar protein, regulates gene transcription. Here, we identify that NCL is expressed exclusively in the nuclei of DRG neurons. Peripheral nerve injury time-dependently upregulates Ncl mRNA and NCL protein levels in injured DRG neurons. Blocking this upregulation through DRG microinjection of the adeno-associated virus 9 (AAV9) expressing an shRNA targeting Ncl attenuates nerve injury-induced increases of C-C motif chemokine ligand 2 (CCL2) mRNA and its protein in injured DRG and alleviates the development and maintenance of mechanical, heat and cold hypersensitivities. Conversely, mimicking DRG NCL upregulation through DRG microinjection of AAV9 carrying the full-length Ncl coding sequence increases Ccl2 mRNA and CCL2 protein levels in microinjected DRGs and produces neuropathic pain-like symptoms in the absence of nerve injury. Mechanistically, peripheral nerve injury increases NCL occupancy at the Ccl2 promoter and enhances chromatin accessibility at this locus, resulting in elevated CCL2 expression in injured DRG neurons, which is reversed by NCL knockdown. Given that Ncl mRNA is co-expressed with Ccl2 mRNA in individual DRG neurons, our findings suggest that NCL upregulation in the DRG contributes to neuropathic pain likely by increasing chromatin accessibility at the Ccl2 promoter in primary sensory neurons.

Animals↗
PubMed2026

Integrative analysis of transcriptome and chromatin accessibility reveals promoter-proximal regulation and identifies candidate ABC transporters associated with cold stress responses in maize.

BACKGROUND: Low-temperature stress is a formidable environmental constraint that severely limits the growth and productivity of maize (Zea mays L.), particularly during the highly vulnerable early seedling stage. While cold tolerance is a critical agronomic objective, the integrated transcriptional and epigenetic regulatory mechanisms that govern this trait remain largely elusive. Characterizing these coordinated molecular networks is fundamental to the genetic enhancement of cold resilience in maize. METHODS: Using two maize inbred lines contrasting in chilling response (ZHB12 tolerant, B73 sensitive), we performed integrative time‑course RNA‑seq and ATAC‑seq to thoroughly and systematically characterize the precise dynamic interplay between gene expression and chromatin accessibility under cold stress conditions at the seedling stage. RESULTS: Physiological assessments confirmed that ZHB12 possesses superior cold tolerance, manifested by significantly attenuated electrolyte leakage and reduced foliar damage compared to B73. Transcriptomic profiling revealed a massive, time-dependent divergence in gene expression between the two genotypes, with a major regulatory transition identified at 24 h of cold exposure. Functional enrichment analysis demonstrated that ZHB12 preferentially activates a robust defense repertoire, including Photosystem II electron transport, diterpenoid biosynthesis, and ATP biosynthetic pathways. Notably, multiple ATP-binding cassette (ABC) transporter genes were coordinately upregulated under chilling, suggesting their potential involvement in cellular homeostasis. ATAC-seq analysis indicated that cold stress is associated with chromatin remodeling in ZHB12, with increased accessibility observed in proximal promoter regions. Integrative analysis identified a core set of dual-responsive genes, in which increased promoter accessibility coincided with transcriptional upregulation. These genes were predominantly enriched in transporter activity and transcriptional regulation, suggesting potential epigenetic link to the superior stress response of ZHB12. CONCLUSION: Our findings reveal extensive transcriptional and chromatin accessibility changes in ZHB12 under cold stress. The observed associations between promoter accessibility and gene activation, particularly in genes involved in transport processes, highlight candidate regulators potentially contributing to cold tolerance. This study provides a molecular framework and identifies high-value candidate genes that may inform future efforts in breeding cold-tolerant maize, pending functional validation.

Zea mays↗
PubMed2023

H3.3 contributes to chromatin accessibility and transcription factor binding at promoter-proximal regulatory elements in embryonic stem cells.

BACKGROUND: The histone variant H3.3 is enriched at active regulatory elements such as promoters and enhancers in mammalian genomes. These regions are highly accessible, creating an environment that is permissive to transcription factor binding and the recruitment of transcriptional coactivators that establish a unique chromatin post-translational landscape. How H3.3 contributes to the establishment and function of chromatin states at these regions is poorly understood. RESULTS: We perform genomic analyses of features associated with active promoter chromatin in mouse embryonic stem cells (ESCs) and find evidence of subtle yet widespread promoter dysregulation in the absence of H3.3. Loss of H3.3 results in reduced chromatin accessibility and transcription factor (TF) binding at promoters of expressed genes in ESCs. Likewise, enrichment of the transcriptional coactivator p300 and downstream histone H3 acetylation at lysine 27 (H3K27ac) is reduced at promoters in the absence of H3.3, along with reduced enrichment of the acetyl lysine reader BRD4. Despite the observed chromatin dysregulation, H3.3 KO ESCs maintain transcription from ESC-specific genes. However, upon undirected differentiation, H3.3 KO cells retain footprinting of ESC-specific TF motifs and fail to generate footprints of lineage-specific TF motifs, in line with their diminished capacity to differentiate. CONCLUSIONS: H3.3 facilitates DNA accessibility, transcription factor binding, and histone post-translational modification at active promoters. While H3.3 is not required for maintaining transcription in ESCs, it does promote de novo transcription factor binding which may contribute to the dysregulation of cellular differentiation in the absence of H3.3.

Animals↗
PubMed2003

p53 is a chromatin accessibility factor for nucleotide excision repair of DNA damage.

One of the longest standing problems in DNA repair is how cells relax chromatin in order to make DNA lesions accessible for global nucleotide excision repair (NER). Since chromatin has to be relaxed for efficient lesion detection, the key question is whether chromatin relaxation precedes lesion detection or vice versa. Chromatin accessibility factors have been proposed but not yet identified. Here we show that p53 acts as a chromatin accessibility factor, mediating UV-induced global chromatin relaxation. Using localized subnuclear UV irradiation, we demonstrate that chromatin relaxation is extended over the whole nucleus and that this process requires p53. We show that the sequence for initiation of global NER is as follows: transcription-associated lesion detection; p53-mediated global chromatin relaxation; and global lesion detection. The tumour suppressor p53 is crucial for genomic stability, a role partially explained by its pro-apoptotic capacity. We demonstrate here that p53 is also a fundamental component of DNA repair, playing a direct role in rectifying DNA damage.

Acetylation↗
PubMed2006

An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses.

Phosphorylation of histone H3 at Ser10 increases chromatin accessibility to transcription factor NF-kappaB on a subset of genes involved in immune responses. Here we report that a bacterial pathogen abrogated phosphorylation of histone H3 to 'shape' the transcriptional responses of infected host cells. We identify the Shigella flexneri protein effector OspF as a dually specific phosphatase that dephosphorylated mitogen-activated protein kinases in the nucleus, thus preventing histone H3 phosphorylation at Ser10 in a gene-specific way. That activity of OspF enabled shigella to block the activation of a subset of NF-kappaB-responsive genes, leading to compromised recruitment of polymorphonuclear leukocytes to infected tissues. S. flexneri has thus evolved the capacity to precisely modulate host cell epigenetic 'information' as a strategy for repressing innate immunity.

Bacterial Outer Membrane Proteins↗
PubMed2005

A bisanthracycline (WP631) represses uPAR gene expression and cell migration of RKO colon cancer cells by interfering with transcription factor binding to a chromatin-accessible -148/-124 promoter region.

The urokinase receptor (uPAR), transcriptionally activated in several cancers, contributes to tumor progression by promoting cell migration and proteolysis, and repressing expression of this gene could be of therapeutic utility. Indeed, targeting regulatory element(s) in the promoter may represent an efficient means for reducing expression because only two alleles have to be neutralized. We previously identified the -148/-124 promoter region, bound with Sp1 and Sp3, as regulatory for uPAR expression in vitro. The purpose of this study was twofold: to determine (a) the accessibility of this region in its natural chromatin setting and (b) the efficacy of WP631, a bisintercalator favoring GC-rich DNA sequences, in repressing endogenous uPAR expression in RKO colon cancer cells. In these cells, DNaseI hypersensitivity, genomic footprinting, and chromatin immunoprecipitation experiments revealed that the -148/-124 uPAR promoter region was accessible in chromatin and bound with Sp1, thus validating it as a therapeutic target. WP631 treatment competed for transcription factor binding to this regulatory region and reduced uPAR mRNA/protein. However, a chemically related compound (WP629), with low DNA binding affinity, failed to diminish uPAR protein amount. GAPDH mRNA level was only modestly affected by WP631, arguing against the possibility that this bisanthracycline universally represses expression of GC-rich promoter-driven genes. Further, uPAR function, as assessed by migration of cells across a vitronectin-coated filter, was attenuated with WP631. Thus, we have shown that the chromatinized -148/-124 regulatory region of the uPAR promoter is accessible to small molecules and that WP631, which disrupts the interaction of DNA binding proteins with this region, diminishes uPAR expression and function.

Antibiotics, Antineoplastic↗
PubMed2005

Histone acetylation increases chromatin accessibility.

In eukaryotes, the interaction of DNA with proteins and supramolecular complexes involved in gene expression is controlled by the dynamic organization of chromatin inasmuch as it defines the DNA accessibility. Here, the nuclear distribution of microinjected fluorescein-labeled dextrans of 42 kDa to 2.5 MDa molecular mass was used to characterize the chromatin accessibility in dependence on histone acetylation. Measurements of the fluorescein-dextran sizes were combined with an image correlation spectroscopy analysis, and three different interphase chromatin condensation states with apparent pore sizes of 16-20 nm, 36-56 nm and 60-100 nm were identified. A reversible change of the chromatin conformation to a uniform 60-100 nm pore size distribution was observed upon increased histone acetylation. This result identifies histone acetylation as a central factor in the dynamic regulation of chromatin accessibility during interphase. In mitotic chromosomes, the chromatin exclusion limit was 10-20 nm and independent of the histone acetylation state.

Acetylation↗
PubMed2000

K562 cells implicate increased chromatin accessibility in Alu transcriptional activation.

Alu repeats in K562 cells are unusually hypomethylated and far more actively transcribed than those in other human cell lines and somatic tissues. Also, the level of Alu RNA in K562 cells is relatively insensitive to cell stresses, namely heat shock, adenovirus infection and treatment with cycloheximide, which increase the abundance of Alu RNA in HeLa and 293 cells. Recent advances in understanding the interactions between DNA methylation, transcriptional activation and chromatin conformation reveal reasons for the constitutively high level of Alu expression in K562 cells. Methylation represses transcription of transiently transfected Alu templates in all cell lines tested but cell stresses do not relieve this repression suggesting that they activate Alu transcription through another pathway. A relatively large fraction of the Alus within K562 chromatin is accessible to restriction enzyme cleavage and cell stresses increase the chromatin accessibility of Alus in HeLa and 293 cells. Cell stress evidently activates Alu transcription by rapidly remodeling chromatin to recruit additional templates.

Adenoviridae↗
PubMed2000

Two histone fold proteins, CHRAC-14 and CHRAC-16, are developmentally regulated subunits of chromatin accessibility complex (CHRAC).

The ISWI ATPase of Drosophila is a molecular engine that can drive a range of nucleosome remodelling reactions in vitro. ISWI is important for cell viability, developmental gene expression and chromosome structure. It interacts with other proteins to form several distinct nucleosome remodelling machines. The chromatin accessibility complex (CHRAC) is a biochemical entity containing ISWI in association with several other proteins. Here we report on the identification of the two smallest CHRAC subunits, CHRAC-14 and CHRAC-16. They contain histone fold domains most closely related to those found in sequence-specific transcription factors NF-YB and NF-YC, respectively. CHRAC-14 and CHRAC-16 interact directly with each other as well as with ISWI, and are associated with functionally active CHRAC. The developmental expression profiles of both subunits suggest specialized roles in chromatin remodelling reactions in the early embryo for both histone fold subunits.

Adenosine Triphosphatases↗
PubMed1998

In vitro chromatin remodelling by chromatin accessibility complex (CHRAC) at the SV40 origin of DNA replication.

DNA replication is initiated by binding of initiation factors to the origin of replication. Nucleosomes are known to inhibit the access of the replication machinery to origin sequences. Recently, nucleosome remodelling factors have been identified that increase the accessibility of nucleosomal DNA to transcription regulators. To test whether the initiation of DNA replication from an origin covered by nucleosomes would also benefit from the action of nucleosome remodelling factors, we reconstituted SV40 DNA into chromatin in Drosophila embryo extracts. In the presence of T-antigen and ATP, a chromatin-associated cofactor allowed efficient replication from a nucleosomal origin in vitro. In search of the energy-dependent cofactor responsible we found that purified 'chromatin accessibility complex' (CHRAC) was able to alter the nucleosomal structure at the origin allowing the binding of T-antigen and efficient initiation of replication. These experiments provide evidence for the involvement of a nucleosome remodelling machine in structural changes at the SV40 origin of DNA replication in vitro.

Animals↗
PubMed1997

Global alterations in chromatin accessibility associated with loss of SIN4 function.

Sin4p is a component of a mediator complex associated with the C-terminal domain of RNA polymerase II and SIN4 is required for proper regulation of several genes in yeast, including the HO endonuclease gene, glucose repressible genes and MATa cell-specific genes. Previous studies indicated that SIN4 may influence transcription through changes in the organization of chromatin. We have examined a specific chromatin structure associated with MATa cell-specific repression in sin4 MATalpha cells to determine if SIN4 is required for nucleosome positioning. Although the loss of SIN4 has no effect on nucleosome location, we find that the sensitivity of bulk chromatin from sin4 cells to micrococcal nuclease digestion is strikingly increased relative to chromatin from isogenic wild-type cells. The nuclease hypersensitivity of chromatin from sin4 cells is not related to gross alterations in histone gene expression or to bulk increases in histone modification. Our experiments suggest that SIN4 directly or indirectly regulates a global aspect of chromatin accessibility, providing a molecular basis for phenotypic similarities between sin4 mutations and mutations in histones.

Chromatin↗
PubMed2006

Stage-specific expression of two neighboring Crlz1 and IgJ genes during B cell development is regulated by their chromatin accessibility and histone acetylation.

The IgJ gene is expressed in the plasma cell stage. However, its neighboring charged amino acid-rich leucine zipper 1 (Crlz1) gene, which is mapped 30 kb upstream of the IgJ gene in mice, is shown to be expressed in the pre-B cell stage. These stage-specific expressions of two neighboring genes are found to be regulated by their chromatin accessibility and acetylation. Hypersensitive site 1 on the IgJ promoter is opened in the plasma cells, whereas hypersensitive sites 9/10 on the Crlz1 promoter are opened in the pre-B cells. Furthermore, H3 and H4 histones toward the chromatin of the Crlz1 gene are found to be hyperacetylated, especially on H3, in the pre-B cells, whereas those toward the chromatin of the IgJ gene are found to be hyperacetylated in the plasma cells. Consistently, the hyperacetylation of H3 and H4 toward the chromatin of the IgJ gene but not the Crlz1 gene is induced by an IL-2 treatment of BCL1, which is a model cell line for studying the terminal differentiation of B cells.

Acetylation↗
PubMed1996

Variegated expression of a globin transgene correlates with chromatin accessibility but not methylation status.

There are now many mammalian examples in which single cell assays of transgene activity have revealed variegated patterns of expression. We have previously reported that transgenes in which globin regulatory elements drive the lacZ reporter gene exhibit variegated expression patterns in mouse erythrocytes, with transgene activity detectable in only a sub-population of circulating erythroid cells. In order to elucidate the molecular mechanism responsible for variegated expression in this system, we have compared the chromatin structure and methylation status of the transgene locus in expressing and non-expressing populations of erythrocytes. We find that there is a difference in the chromatin conformation of the transgene locus between the two states. Relative to active transgenes, transgene loci which have been silenced exhibit a reduced sensitivity to general digestion by DNase I, as well as a failure to establish a transgene-specific DNase I hypersensitive site, suggesting that silenced transgenes are situated within less accessible chromatin structures. Surprisingly, the restrictive chromatin structure observed at silenced transgene loci did not correlate with increased methylation, with transgenes from both active and inactive loci appearing largely unmethylated following analysis with methylation-sensitive restriction enzymes and by sequencing PCR products derived from bisulphite-converted genomic DNA.

Animals↗
PubMed2005

The Ig kappa 3' enhancer is activated by gradients of chromatin accessibility and protein association.

The Igkappa locus is recombined following initiation of a signaling cascade during the early pre-B stage of B cell development. The Ig kappa3' enhancer plays an important role in normal B cell development by regulating kappa locus activation. Quantitative analyses of kappa3' enhancer chromatin structure by restriction endonuclease accessibility and protein association by chromatin immunoprecipitation in a developmental series of primary murine B cells and murine B cell lines demonstrate that the enhancer is activated progressively through multiple steps as cells mature. Moderate kappa3' chromatin accessibility and low levels of protein association in pro-B cells are increased substantially as the cells progress from pro- to pre-B, then eventually mature B cell stages. Chromatin immunoprecipitation assays suggest transcriptional regulators of the kappa3' enhancer, specifically PU.1 and IFN regulatory factor-4, exploit enhanced accessibility by increasing association as cells mature. Characterization of histone acetylation patterns at the kappa3' enhancer and experimental inhibition of histone deacetylation suggest changes therein may determine changes in enzyme and transcription factor accessibility. This analysis demonstrates kappa activation is a multistep process initiated in early B cell precursors before Igmu recombination and finalized only after the pre-B cell stage.

3' Untranslated Regions↗