Biology subjects

Tremethick, D.

Publications and source records attributed to Tremethick, D..

5 recordsLinked to original sources

bioRxiv2026

HP1α depletion and TGFβ activation exert antagonistic effects on 3D genome organization

The three-dimensional (3D) organization of the human genome plays a critical role in regulating gene expression and is frequently disrupted in cancer. However, how key factors like Heterochromatin Protein 1 alpha (HP1) and Transforming Growth Factor beta (TGF{beta}) remodel this architecture to drive tumorigenesis remains poorly understood. We investigated the effects of HP1 knockdown and TGF{beta} treatment on higher-order chromatin structure and gene expression in human mammary epithelial cells. Our findings reveal that HP1 depletion and TGF{beta} stimulation exert distinct and opposing effects on genome compartmentalization and sub compartmentalization. HP1 knockdown drives a genome-wide shift of chromatin from transcriptionally inactive B compartments to active A compartments. This is accompanied by a stepwise redistribution of A subcompartments toward the most transcriptionally active state (A3), and the upregulation of oncogenic genes involved in EMT and proliferation. In contrast, TGF{beta} treatment promotes chromatin compaction, increases the proportion of B compartments, and drives a stepwise reduction in active A subcompartments. Our results highlight the differential roles of HP1 and TGF{beta} in shaping the 3D genome and underscore how precise, stepwise architectural changes contribute to malignant transformation. This study provides critical insight into how chromatin architecture acts as a regulatory layer in breast cancer development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/705282v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@11c7475org.highwire.dtl.DTLVardef@121b305org.highwire.dtl.DTLVardef@1704b64org.highwire.dtl.DTLVardef@1659c34_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

genomics↗

bioRxiv2023

Multi-level 3D genome organization deteriorates during breast cancer progression

Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that while the fundamental properties of topologically associating domains (TADs) are overall maintained, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observe a restructuring of TAD-TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identify a previously unrecognized interchromosomal insertion event, wherein a locus on chromosome 8 housing the MYC oncogene is inserted into a highly active subcompartment on chromosome 10. This insertion is accompanied by the formation of de novo enhancer contacts and activation of MYC, illustrating how structural genomic variants can alter the 3D genome to drive oncogenic states. In summary, our findings provide evidence for the loss of genome organization at multiple scales during breast cancer progression revealing novel relationships between genome 3D structure and oncogenic processes.

genomics↗

bioRxiv2021

H2AFB1 is a cancer/testis gene involved in hyperactivation of ribosome biogenesis in Hodgkin Lymphoma

Testis-specific regulators of chromatin function are commonly ectopically expressed in human cancers, but their roles are poorly understood. Examination of 81 primary Hodgkin Lymphoma (HL) samples showed that the ectopic expression of the eutherian testis-specific histone variant H2A.B is an inherent feature of HL. In experiments using two HL-derived cell lines derived from different subtypes of HL, H2A.B knockdown inhibited cell proliferation. H2A.B was enriched in both the nucleoli of these HL cell lines and primary HL samples. We found that H2A.B enhanced ribosomal DNA (rDNA) transcription, was enriched at the rDNA promoter and transcribed regions, and interacted with RNA Pol I. Depletion of H2A.B caused the loss of RNA Pol I from rDNA chromatin. Remarkably, H2A.B was also required for high levels of ribosomal protein gene expression being located at the transcriptional start site and within the gene body. H2A.B knockdown reduced gene body chromatin accessibility of active RNA Pol II genes concurrent with a decrease in transcription. Taken together, our data show that in HL H2A.B has acquired a new function, the ability to increase ribosome biogenesis.

genomics↗

bioRxiv2017

Gene editing of the multi-copy H2A.B gene family by a single pair of TALENS

In view of the controversy related to the generation of off-target mutations by gene editing approaches, we tested the specificity of TALENs by disrupting a multi-copy gene family using only one pair of TALENS. We show here that TALENS do display a high level of specificity by simultaneously knocking out the function of the three genes that encode for H2A.B.3. This represents the first described knockout of this histone variant.

genomics↗

bioRxiv2017

POWERDRESS-mediated histone deacetylation is essential for thermomorphogenesis in Arabidopsis thaliana

Ambient temperature influences plant growth and development and minor changes can substantially impact crop yields. The underlying mechanisms for temperature perception and response are just beginning to emerge. Chromatin remodeling via the eviction of the histone variant H2A.Z in nucleosomes that alters gene expression is a critical component of thermal response in plants. However, whether chromatin-remodeling processes such as histone modifications play a global role in thermal response remains unknown. Using a combination of genetic analysis, chemical inhibition studies and RNA-seq analysis coupled with meta-analysis, here we identify POWERDRESS (PWR), a SANT-domain containing protein that is known to interact with HISTONE DEACETYLASE 9 (HDA9), as a novel key factor required for thermomorphogenesis in Arabidopsis thaliana. We identify that mutations in PWR impede thermomorphogenesis exemplified by severely attenuated temperature-induced hypocotyl/petiole elongation and early flowering. We show that inhibitors of histone deacetylases diminish temperature-induced hypocotyl elongation, which demonstrates for the first time a requirement for histone deacetylation in thermomorphogenesis. Genes that are misregulated in pwr mutants showed enrichment for GO terms associated with \"response\". Our expression studies coupled with meta-analysis revealed a significant overlap between genes misregulated in pwr mutants and genes that are enriched for H2A.Z in their gene bodies. Meta-analyses reveal that genes misregulated in pwr mutants in diverse conditions also overlap with genes that are differentially expressed in the mutants of the components of the SWR1 complex that mediates H2A.Z nucleosome dynamics. Our findings thus uncover a role for PWR in facilitating thermal response and suggest a potential link between histone deacetylation and H2A.Z nucleosome dynamics in regulation of gene expression in plants.\n\nAuthor summaryPlant growth and development is influenced by a variety of external environmental cues. Ambient temperature affects almost all stages of plant development but the underlying molecular mechanisms remain largely unknown. In this paper, the authors show that histone deacetylation, one of the major chromatin remodeling processes, is essential for eliciting growth temperature-induced responses in plants. The authors identify POWERDRESS, a protein known to interact with HISTONE DEACETYLASE 9, as a novel key player essential for eliciting high temperature induced responses in Arabidopsis. Another chromatin remodeling mechanism that is known to play a role in thermal response is the eviction of histone variant H2A.Z from nucleosomes. Through transcriptome studies the authors demonstrate an overlap between gene regulations conferred through PWR-mediated histone H3 deacetylation and that conferred via histone H2A.Z eviction/incorporation dynamics. This study identifies a key novel gene that is essential for plants to elicit high temperature responses and reveals close links between two seemingly distinct chromatin-remodeling processes in regulating gene expression in plants.

genetics↗