Biology subjects

Zhangding, Z.

Publications and source records attributed to Zhangding, Z..

3 recordsLinked to original sources

bioRxiv2025

Characterizing trajectory-like chromatin architectures with Fun2

Chromatin is intricately folded into dynamic 3D structures, orchestrating key DNA metabolic processes. DNA replication, a core chromatin metabolic event, is tightly linked to these chromatin architectures. Recently, a replication-associated chromatin interaction structure was discovered as fountains via Replication-associated in situ Hi-C (Repli-HiC), supporting that replication forks remain spatially coupled from initiation to termination. Chromatin fountains are pivotal for understanding DNA replication within the complex chromatin landscape. However, the characteristics of these fountains can vary due to factors such as origin firing efficiency and local chromatin organization. In this study, we introduce a reinforcement learning-based computational framework, integrated with Monte Carlo Tree Search (MCTS) and value gradient optimization, to develop the Fun2 algorithm. Fun2 enables a comprehensive characterization of trajectory-like chromatin architectures, including both chromatin fountains and stripes, with enhanced adaptability and accuracy. This tool facilitates systematic investigation of the spatiotemporal dynamics of DNA replication and extends to other chromatin remodeling processes, such as Cohesin-mediated loop extrusion. The Fun2 algorithm provides a versatile computational tool for deciphering dynamic chromatin architectures, offering new insights into genome organization and its regulatory mechanisms.

bioinformatics↗

bioRxiv2023

Genome editing induces the transfer of mitochondrial DNA into the nuclear genome

Mitochondria serve as the cellular powerhouse, and their distinct DNA makes them a prospective target for gene editing to treat genetic disorders. However, the impact of genome editing on mitochondrial DNA (mtDNA) stability remains a mystery. Our study reveals previously unknown risks of genome editing that both nuclear and mitochondrial editing cause broad transfer of mitochondrial DNA segments into the nuclear genome in various cell types including human cell lines, primary T cells, retinal cells, and mouse embryos. Furthermore, drug-induced mitochondrial stresses and mtDNA breaks exacerbate this transfer of mtDNA into the nuclear genome. Notably, we observe that the newly developed mitochondrial base editor DdCBE can also cause widespread mtDNA integrations. However, we provide a practical solution to suppress the transfer of mtDNA by co-expressing TREX1 or TREX2 exonucleases during DdCBE editing. These findings also shed light on the origins of mitochondrial-nuclear DNA segments.

genomics↗

bioRxiv2021

Cohesin modulates DNA replication to preserve genome integrity

Cohesin participates in loop formation by extruding DNA fibers from its ring-shaped structure. Cohesin dysfunction eliminates chromatin loops but only causes modest transcription perturbation, which cannot fully explain the frequently observed mutations of cohesin in various cancers. Here, we found that DNA replication initiates at more than one thousand extra dormant origins after acute depletion of RAD21, a core subunit of cohesin, resulting in earlier replicating timing at approximately 30% of the human genomic regions. In contrast, CTCF is dispensable for suppressing the early firing of dormant origins that are distributed away from the loop boundaries. Furthermore, greatly elevated levels of gross DNA breaks and genome-wide chromosomal translocations arise in RAD21-depleted cells, accompanied by dysregulated replication timing at dozens of hotspot genes. Thus, we conclude that cohesin coordinates DNA replication initiation to ensure proper replication timing and safeguards genome integrity.

genetics↗