Fully T2T pedigree assemblies reveal genetic stability and epigenetic plasticity of human centromeres across inheritance and cell-fate transitions
Year: 2026
Type: preprint
Abstract: Centromeres are essential chromosome components yet remain poorly understood due to their highly repetitive sequence architecture. Using fully-phased telomere-to-telomere diploid assemblies from a three-generation pedigree integrated with long-read epigenomes from matched peripheral blood mononuclear cells, induced pluripotent stem cells, and neural progenitor cells, we generate allele-resolved single basepair resolution maps of centromere genetic and epigenetic dynamics across inheritance, reprogramming, and differentiation. We show that centromeric dip regions (CDRs), which define the functional core of centromeres, are positionally stable across generations and cell-fate transitions. In contrast, CDR epigenetic architecture is highly dynamic. Reprogramming markedly attenuates CDR hypomethylation, which is partially restored during differentiation in parallel with global hypomethylation of active alpha-satellite arrays and coordinated changes in nucleosome organization and protein occupancy. Centromeric remodeling is insulated from X-chromosome status, including Xa, Xi, and erosion. Finally, de novo mutations arising during reprogramming are enriched in centromeric regions but depleted within functional centromeric cores.
Authors: Shihua Dong, Xiaoyun Xing, Monika Cechova, Hailey Loucks, Selvamani Vijayalingam, Amber Neilson, Monica Sentmanat, Juan Macias, Tianjie Liu, Zheng Dong, Benpeng Miao, Wenjin Zhang, Chad Tomlinson, Heather Schmidt, Edward A. Belter, Ming Hu, Xiaoxia Cui, Nathan O. Stitziel, Karen H. Miga, Ting Wang
Language: English
Subfield: Plant Science
Domain: Life Sciences
Open Access status: green
Awards: DECODING THE IMPACT OF TRANSPOSABLE ELEMENTS ON GENE REGULATION, Center for Human Reference Genome Diversity, Model-based methods for single cell chromatin interactomic data, Center for Human Genome Reference Diversity, WashU-Northwestern Genomic Variation and Function Data and Administrative Coordinating Center, The Human Pangenome Reference Consortium Coordination Center
OpenAlex ID: W7129776315