Research

Genetic architecture of age-related chronic diseases

Genetic predisposition is critical for complex human diseases. In my latest study, I 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).

Cell type-specific epigenetic regulatory elements

Epigenetic regulatory elements play important roles in cell fate determination. To identify these elements, I 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); QDCMR for identifying differential chromatin regions from ChIP-seq data (Liu et al. 2013 Sci. Rep.; 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, I 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).

Epigenetic dynamics in mammalian development

Epigenetic marking systems confer precise regulation of gene expression during mammalian development. 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; Liu et al. In preparation). These studies highlighted locus-specific convergence of genetic, epigenetic, and developmental elements in disease development.

Cellular origins of age-related chronic diseases

The causal cell type and regulatory mechanisms are poorly understood for complex diseases. To identify cell types causally associated with kidney disease, we generated single-nucleus transposase-accessible chromatin with sequencing (snATAC-seq), single-cell RNA sequencing (scRNA), and spatially resolved transcriptomics in mouse and human kidneys. The analysis of these single-cell resolution datasets 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; Amin,…, Liu et al. 2022 BioRxiv).