Biology subjects

Wang, X. Q. D.

Publications and source records attributed to Wang, X. Q. D..

4 recordsLinked to original sources

bioRxiv2025

Pan-cancer 3D genomic analysis revealed extremely long Polycomb loops as the biomarker for sensitivity to Polycomb inhibition

Polycomb targeted loci form long-range chromatin interactions independent of CTCF-cohesion and are demarcated by low DNA methylation(1-3). Polycomb targets form extremely long-range loops (long Polycomb loops) that can separate anchors up to 60 Mb. These loops predominantly occur in cells of self-renewal status, such as human hematopoietic stem cells (HSC) and mouse embryonic stem cells (ESC), but rarely in cell lines. To identify long Polycomb loops in cancer, we initiated a pan-cancer survey of long Polycomb loops in a collection of 264 tumor samples (33 acute myeloid leukemias, 17 T cell lymphoblastic leukemia, 29 Breast cancer samples, 63 pediatric brain tumors, 70 prostate cancers, and 42 colon cancers). We found most cancers, including all prostate cancers and colon cancers, lack long Polycomb loops except pediatric brain tumors and certain AMLs. In pediatric brain tumors, we found 30% of the ependymoma PFA subtype (which shows globally depleted H3K27me3) notably displayed strong long Polycomb loop interactions. AML displayed more diverse levels of long Polycomb loop interactions. Most AMLs lost both long Polycomb loops with Polycomb binding loss at the loop anchors. Whereas 10% of AMLs retain long Polycomb loops as strong as in HSCs. These AMLs recurrently carry mutations in CEBPA and STAG2, which are not associated with the Polycomb complex or DNA methylation machinery. We found that long Polycomb loop strong AML is sensitive to EZH2 inhibition, which induces cell differentiation. Conversely, PRC1 component dependency can be used to predict long Polycomb loop formation in B-cell lymphoblastic leukemia cell lines. Our analysis suggests that the oncogenesis process antagonizes the long Polycomb loop maintenance in most cancers, yet certain cancers may still preserve strong long Polycomb loops from cell-of-origin. The maintenance of long Polycomb loops sensitizes cells to Polycomb inhibition, indicating that such loops could be an epigenomic biomarker for pharmacological or genetic Polycomb inhibition.

cancer biology↗

bioRxiv2021

3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression

Mutations in the adult {beta}-globin gene can lead to a variety of hemoglobinopathies, including sickle cell disease and {beta}-thalassemia. An increase in fetal hemoglobin expression throughout adulthood, a condition named Hereditary Persistence of Fetal Hemoglobin (HPFH), has been found to ameliorate hemoglobinopathies. Deletional HPFH occurs through the excision of a significant portion of the 3 end of the {beta}-globin locus, including a CTCF binding site termed 3HS1. Here, we show that the deletion of this CTCF site alone induces fetal hemoglobin expression in both adult CD34+ hematopoietic stem and progenitor cells and HUDEP-2 erythroid progenitor cells. This induction is driven by the ectopic access of a previously postulated distal enhancer located in the OR52A1 gene downstream of the locus, which can also be insulated by the inversion of the 3HS1 CTCF site. This suggests that genetic editing of this binding site can have therapeutic implications to treat hemoglobinopathies.

genomics↗

bioRxiv2020

Connecting high-resolution 3D chromatin organization with epigenomics

The resolution of chromatin conformation capture technologies keeps increasing, and the recent nucleosome resolution chromatin contact maps allow us to explore how fine-scale 3D chromatin organization is related to epigenomic states in human cells. Using publicly available Micro-C datasets, we have developed a deep learning model, CAESAR, to learn a mapping function from epigenomic features to 3D chromatin organization. The model accurately predicts fine-scale structures, such as short-range chromatin loops and stripes, that Hi-C fails to detect. With existing epigenomic datasets from ENCODE and Roadmap Epigenomics Project, we successfully imputed high-resolution 3D chromatin contact maps for 91 human tissues and cell lines. In the imputed high-resolution contact maps, we identified the spatial interactions between genes and their experimentally validated regulatory elements, demonstrating CAESARs potential in coupling transcriptional regulation with 3D chromatin organization at high resolution.

bioinformatics↗

bioRxiv2020

Three-dimensional regulation of HOXA cluster genes by a cis-element in hematopoietic stem cell and leukemia.

Proper gene regulation is crucial for cellular differentiation, and dysregulation of key genes can lead to diseased states such as cancer. The HOX transcription factors play such a role during hematopoiesis, and aberrant expression of certain HOXA genes is found in certain acute myeloid leukemias (AMLs). While studies have shown that these genes are targeted by a variety of mutant proteins including mutant NPM1, MLL fusions, and NUP98 fusions, little is known about how long-range 3D chromatin interactions regulate the HOXA genes in normal hematopoiesis and leukemia. Here, we report the interaction between the HOXA cluster with a [~]1.3 Mb upstream DNA methylation Canyon termed "Geneless Canyon" (GLC) in human CD34+/CD38-hematopoietic stem cells (HSCs) and AML cell lines. We show that CRISPR-Cas9 mediated deletion of the whole GLC region reduces the expression of the distal HOXA genes and compromises HSC and leukemia cells self-renewal. This long-range chromatin interaction brings the HOXA cluster in contact with the nuclear pore complex (NPC) at the nuclear periphery, which promotes HOXA gene expression and maintains HSC and leukemia cell self-renewal. These findings reveal how long-range 3D chromatin organization regulates key transcription factor genes in both normal and diseased hematopoietic cells.

genomics↗