Biology subjects

Wang, G. G.

Publications and source records attributed to Wang, G. G..

9 recordsLinked to original sources

bioRxiv2025

Stress-induced loss of CTCF reveals an alternative, promoter-based mode of cohesin looping

Cells continually face environmental stressors that challenge homeostasis, yet how three-dimensional (3D) chromatin structure contributes to these stress responses remains unclear under hyperosmotic conditions. To investigate this, we map 3D chromatin structure, its molecular drivers, and transcriptional outcomes during sorbitol-induced hyperosmotic stress. Within 1 hour of sorbitol treatment, pre-existing loops and domains collapse, while several hundred de novo sorbitol-induced loops emerge. These loops are punctate, longer-range, and transient. 3D chromatin structure largely returns to baseline conditions by 24 hours. Loop reorganization is consistent across cell types and hyperosmotic stimuli. Sorbitol-induced loops require cohesin but not CTCF, and anchors are enriched at active promoters harboring GC-rich transcription factor motifs. Genes at these anchors show delayed activation following loop formation, consistent with loops acting upstream of transcription. Together, hyperosmotic stress triggers rapid, reversible, CTCF-independent chromatin reorganization that correlates with transcriptional adaptation.

genomics↗

bioRxiv2025

YY1 relieves p300 autoinhibition to promote histone acetylation in advanced prostate cancer, enhancing the oncogenic signaling of Androgen Receptor Splice Variant 7

Genetic and epigenetic aberrations often act in concert to establish oncogenic transcriptomic programs in aggressive cancers. For example, the development of castration-resistant prostate cancer (CRPC), an advanced prostate cancer form, is closely associated with over-expression and/or hyper-activation of transcription factors (TFs) such as Androgen Receptor (AR) and Yin Yang 1 (YY1), as well as p300, a prominent histone acetyltransferase. How exactly these cancer-related lesions are coordinated to generate a malignant cell state remains elusive. Here, we demonstrate that YY1, which is frequently over-expressed in advanced prostate cancers, allosterically stimulates the acetyltransferase activity of p300 in cis, leading to the globally elevated acetylation of histone H3 lysine 18 and 27 (H3K18ac and H3K27ac). Mechanistically, YY1s N-terminal activation domain (AD) directly interacts with p300s TAZ2 domain, relieving the autoinhibition of p300 to facilitate substrate acetylation. Our integrated genome-wide mapping and transcriptomic studies reveal significant co-localization of genomic binding sites of YY1, androgen receptor splice variant 7 (AR-V7, a constitutively active form of AR) and p300 in CRPC cells, where the YY1-mediated p300 activation and resultant histone acetylation increases promote the oncogenic gene-expression programs downstream of YY1 and AR/AR-V7. Both in vitro and in vivo functional assays demonstrate a critical requirement of the above signaling for the advanced disease progression and drug resistance seen in CRPC. Altogether, this study uncovers that YY1 acts to alleviate p300s autoinhibition at target genes co-bound by oncogenic TFs (YY1 and/or AR/AR-V7) in CRPC, thereby sustaining tumorigenicity. Additionally, the blockade of YY1-mediated gene activation resensitizes CRPC to treatment to the clinic anti-AR agent (enzalutamide), which provides a rationale for overcoming the therapeutic resistance often seen in advanced prostate cancers.

cancer biology↗

bioRxiv2025

Epigenetic priming promotes acquisition of tyrosine kinase inhibitor resistance and oncogene amplification in human lung cancer

In mammalian cells, gene copy number is tightly controlled to maintain gene expression and genome stability. However, a common molecular feature across cancer types is oncogene amplification, which promotes cancer progression by drastically increasing the copy number and expression of tumor-promoting genes. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification occurs in over 40% of patients tumors. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the mechanisms facilitating oncogene amplification are not fully understood. Here, we find that LUADs exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naive tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. We identified a global chromatin priming effect during the acquisition of TKI resistance, marked by a dynamic increase of H3K27Ac, cohesin loading, and inter-TAD interactions, which occurs before the onset of oncogene amplification. Furthermore, we have found that the METTL7A protein, which was previously reported to localize to the endoplasmic reticulum and inner nuclear membrane, has a novel chromatin regulatory function by binding to amplified loci and regulating cohesin recruitment and inter-TAD interactions. Surprisingly, we discovered that METTL7A remodels the chromatin landscape prior to large-scale copy number gains. Furthermore, while METTL7A depletion has little effect on the chromatin structure and proliferation of drug-naive cells, METTL7A depletion prevents the formation and maintenance of TKI resistant-clones, highlighting the specific role of METTL7A as cells are becoming resistant. In summary, we discovered an unexpected mechanism required for the acquisition of TKI resistance regulated by a largely uncharacterized factor, METTL7A. This discovery sheds light into the maintenance of oncogene copy number and paves the way to the development of new therapeutics for preventing TKI resistance in LUAD.

genetics↗

bioRxiv2021

A conserved BAH module within mammalian BAHD1 connects H3K27me3 to Polycomb gene silencing

Trimethylation of histone H3 lysine 27 (H3K27me3) is important for gene silencing and imprinting, (epi)genome organization and organismal development. In a prevalent model, the functional readout of H3K27me3 in mammalian cells is achieved through the H3K27me3-recognizing chromodomain harbored within the chromobox (CBX) component of canonical Polycomb repressive complex 1 (cPRC1), which induces chromatin compaction and gene repression. Here, we report that binding of H3K27me3 by a Bromo Adjacent Homology (BAH) domain harbored within BAH domain-containing protein 1 (BAHD1) is required for overall BAHD1 targeting to chromatin and for optimal repression of the H3K27me3-demarcated genes in mammalian cells. Disruption of direct interaction between BAHD1BAH and H3K27me3 by point mutagenesis leads to chromatin remodeling, notably, increased histone acetylation, at its Polycomb gene targets. Mice carrying an H3K27me3-interaction-defective mutation of Bahd1BAH causes marked embryonic lethality, showing a requirement of this pathway for normal development. Altogether, this work demonstrates an H3K27me3-initiated signaling cascade that operates through a conserved BAH "reader" module within BAHD1 in mammals. Key PointsO_LIBAHD1BAH is a functionally validated mammalian "reader" of H3K27me3, mediating BAHD1 targeting for gene silencing. C_LIO_LIBAHD1BAH connects H3K27me3 together with histone deacetylation, an integral step of gene silencing. C_LIO_LIBAHD1BAH-mediated functional readout of H3K27me3 is essential for organismal development. C_LI Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/435004v2_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@1e072a4org.highwire.dtl.DTLVardef@86a86borg.highwire.dtl.DTLVardef@9b1354org.highwire.dtl.DTLVardef@111fa5d_HPS_FORMAT_FIGEXP M_FIG A mammalian H3K27me3-transduction pathway operates through an H3K27me3-specific reader module (BAH) of BAHD1, which assembles a complex with corepressors (HDACs and others) for suppressing histone acetylation and repressing expression at Polycomb target genes. C_FIG

biochemistry↗

bioRxiv2021

REPROGRAMMING CBX8-PRC1 FUNCTION WITH A POSITIVE ALLOSTERIC MODULATOR

ABSTRACTCanonical targeting of Polycomb Repressive Complex 1 (PRC1) to repress developmental genes is mediated by cell type-specific, paralogous chromobox (CBX) proteins (CBX2, 4, 6, 7 and 8). Based on their central role in silencing and their misregulation associated with human disease including cancer, CBX proteins are attractive targets for small molecule chemical probe development. Here, we have used a quantitative and target-specific cellular assay to discover a potent positive allosteric modulator (PAM) of CBX8. The PAM activity of UNC7040 antagonizes H3K27me3 binding by CBX8 while increasing interactions with nucleic acids and participation in variant PRC1. We show that treatment with UNC7040 leads to efficient PRC1 chromatin eviction, loss of silencing and reduced proliferation across different cancer cell lines. Our discovery and characterization of UNC7040 not only revealed the most cellularly potent CBX8-specific chemical probe to date, but also corroborates a mechanism of polycomb regulation by non-histone lysine methylated interaction partners.

synthetic biology↗

bioRxiv2020

YY1 cistrome analysis uncovers an essential requirement of the YY1:BRD4-PFKP regulatory axis for promoting tumorigenesis of castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) is a terminal disease, demanding a better understanding of its pathogenesis. Targeted therapy needs to be developed for CRPC due to its heterogeneity and resistance to current treatments. Here, through cistrome study of YY1, a transcription factor significantly overexpressed during prostate cancer progression, we identify a YY1-PFKP axis to be essential for CRPC tumorigenesis. Depletion of YY1 in independent CRPC models dramatically reduced tumor cell growth in vitro and delayed oncogenic progression in vivo. Importantly, YY1 functions as a master regulator of prostate tumor metabolism including the Warburg effect and mitochondria respiration. Loss-of-function and rescue studies further reveals a mechanistic underpinning in which YY1 directly binds and trans-activates PFKP, a gene encoding the rate-limiting enzyme for glycolysis, significantly contributing to the YY1-enforced oncogenic phenotypes such as enhanced tumor cell glycolysis and malignant growth. Additionally, a vast majority of gene-regulatory element in advanced prostate cancer cells are bound by YY1, lending a support for its role as a master regulator of prostate cancer progression. YY1 interactome studies point to bromodomain-containing coactivators in prostate cancer, which act as functional partners of YY1 to potentiate YY1-related target gene activation. Altogether, this study unveils an unexplored YY1:BRD4-PFKP oncogenic axis operating in advanced prostate cancer with implications for therapy.

cancer biology↗

bioRxiv2020

Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms

Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals crucial and distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.

genetics↗

bioRxiv2020

Direct readout of heterochromatic H3K9me3 regulates DNMT1-mediated maintenance DNA methylation

In mammals, repressive histone modifications such as trimethylation of histone H3 Lys9 (H3K9me3), frequently coexist with DNA methylation, producing a more stable and silenced chromatin state. However, it remains elusive how these epigenetic modifications crosstalk. Here, through structural and biochemical characterizations, we identified the replication foci targeting sequence (RFTS) domain of maintenance DNA methyltransferase DNMT1, a module known to bind the ubiquitylated H3 (H3Ub), as a specific reader for H3K9me3/H3Ub, with the recognition mode distinct from the typical trimethyl-lysine reader. Disruption of the interaction between RFTS and the H3K9me3Ub affects the localization of DNMT1 in stem cells and profoundly impairs the global DNA methylation and genomic stability. Together, this study reveals a previously unappreciated pathway through which H3K9me3 directly reinforces DNMT1-mediated maintenance DNA methylation.

genetics↗

bioRxiv2017

Assessment of the World Largest Afforestation Program: Success, Failure, and Future Directions

The Three-North Afforestation Program (TNAP), initiated in 1978 and scheduled to be completed in 2050, is the worlds largest afforestation project and covers 4.07 x 106 km2 (42.4%) of China. We systematically assessed goals and outcomes of the first 30 years of the TNAP using high-resolution remote sensing and ground survey data. With almost 23 billion dollars invested between 1978 and 2008, the forested area within the TNAP region increased by 1.20 x 107 ha, but the proportion of high quality forests declined by 15.8%. The establishment of shelterbelts improved crop yield by 1.7%, much lower than the 5.9% expected once all crop fields are fully protected by shelterbelts. The area subjected to soil erosion by water decreased by 36.0% from 6.72 x 107 to 4.27 x 107 ha; the largest reductions occurred in areas where soil erosion had been most severe and forests contributed more than half of this improvement. Desertification area increased from 1978 to 2000 but decreased from 2000 to 2008; the 30-year net reduction was 13.0% (4.05x106 ha), with 8.0% being accounted for by afforestation in areas with only slight, prior desertification. In addition to its direct impacts, the TNAP has enhanced peoples awareness of environmental protection and attracted consistent attention and long-term commitment from the Chinese government to the restoration and protection of fragile ecosystems in the vast Three-North region. The significant decline in forest quality, limited success in reducing desertification, and low coverage of shelterbelts are aspects of the TNAP in need of re-assessment, and additional ca. 34 billion dollars will be needed to ensure the completion of the TNAP.

ecology↗