Genetic architecture of age-related chronic diseases



Genetic predisposition is critical for complex human diseases. We performed a comprehensive mapping of genetic architecture of kidney disease by applying large scale GWAS, eQTL and meQTL analysis. I discovered that epigenome (DNA methylation) explains a larger fraction of heritability than gene expression. To further identify disease-causal genes, I proposed a multi-stage prioritization strategy and prioritized >500 kidney disease genes, including SLC47A1, whose causal role was defined in knockout mice model and in human individuals carrying loss-of-function variants. (Liu et al., 2022 Nature Genetics; Project page; Github).

Epigenetic regulation of age-related chronic diseases



Epigenetic regulators play central roles in complex diseases. By applying our bioinformatic tools to large-scale epigenome data, we identified disease-critical epigenetic regulatory elements, including DNA methylation, histone modifications, super-enhancers, and long non-coding RNAs, and explored their roles in complex human diseases (e.g. kidney disease, diabetes, and cancer) (Xu, Liu et al. 2019 Cell Death & Disease; Xiong,…, Liu et al. 2017 NAR; Wei,…, Liu et al. 2016 NAR; Lv, Liu et al. 2013 NAR; Lv, Liu et al. 2012 NAR; Zhang, Liu et al. 2011 NAR; Zhang, Lv, Liu et al. 2010 NAR).

Cellular origins of age-related chronic diseases

The causal cell type and regulatory mechanisms are poorly understood for complex diseases. To identify causal cell types, we developed a series of bioinformatic software, such as SMART for de novo identifying tissue/cell-specific methylated regions from whole genome bisulfite sequencing data (Liu et al. 2016 NAR; Project page); QDMR for identifying differentially methylated regions from array-based methylation data (Zhang, Liu et al. 2011 NAR; Project page). Further, we generated single-nucleus transposase-accessible chromatin with sequencing (snATAC-seq), single-cell RNA sequencing (scRNA), and spatially resolved transcriptomics. The analysis illustrated the crucial roles of kidney cells (e.g., proximal tubule cells) and cell type-specific genes (e.g., SLC47A1) in kidney injury and fibrosis. (Liu et al., 2022 Nature Genetics; Sheng,…,Liu et al., 2021 Nature Genetics; Miao,…, Liu et al. 2021, Nature Comms; Doke,…, Liu et al., 2021 JCI; Dhillion,…, Liu et al., Cell Metabolism; Abedini,…, Liu et al. 2022 BioRxiv).

Epigenetic dynamics in development and aging



Epigenetic marking systems confer precise regulation of gene expression during development and aging. DNA methylation and histone modification undergo dynamics during mammalian development (Liu et al. 2014 Database; Liu et al. 2013 Sci. Rep.). Using knockout mice of Dnmt3a/b, we demonstrated essential roles of DNA methylation in decommissioned fetal enhancers linking to kidney disease (Guan, Liu et al. 2020 JASN). Using knockout mice of Tet2/3, we demonstrated critical roles of hydroxymethylation for nephron progenitor differentiation and nephron endowment (Liang,..., Liu et al. 2023 JASN). These studies highlighted locus-specific convergence of genetic, epigenetic, and developmental elements in disease development.