Our research focus

The primary focus of the Li Lab is on assessing the performance of next-generation sequencing techniques in accurate genome/epigenome/transcriptome profiling and understanding the clinical and functional role of epigenome heterogeneity in the cancer evolution. The Li laboratory utilizes computational and sequencing methodologies to identify and characterize the essential epigenetic lesions that guide cancer cells to evolve and escape from therapy. Our research interest is to understand the inner workings of cancer cells – the genetic and epigenetic heterogeneity that drive cancer initiation and progression. Specifically, the research involves (1) determining the drivers of epigenetic heterogeneity; (2) evaluating the functional impact of the cross-talk among epigenetic modifications on transcriptome; (3) assessing epigenetic heterogeneity/subpopulations in treatment resistance.

Dr. Li has developed a series of computational methods and software for the epigenome sequencing data analysis, to comprehensively detect the significant DNA methylation aberration and epigenetic heterogeneity during disease progression. Dr. Li's work has helped to establish the first principles and metrics for examining changes in RNA splicing and expression profiling and set standards at the FDA for clinical-grade RNA-sequencing. Dr. Li further applied these approaches to study the epigenetic heterogeneity and dynamics using acute myeloid leukemia (AML) as a model. Dr. Li found that epigenetic allele burden was linked to inferior clinical outcome, and epigenetic dynamics was related to hypervariable transcriptional regulation and was divergent from the genetic burden.

Highlighted Abstract

TET2 somatic mutations occur in ∼10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in CREBBP-mutant DLBCLs. Accordingly, TET2 mutation in patients yields a CREBBP-mutant gene-expression signature, CREBBP and TET2 mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies CREBBP somatic mutation. These results advocate for sequencing TET2 in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors.See related commentary by Shingleton and Dave, p. 1515.This article is highlighted in the In This Issue feature, p. 1494.

The Li Lab

Principal Investigator: Sheng Li, Ph.D.

Our research focus

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Selected Publications

Highlighted Abstract

Computing the etiology of cancer

Stuck in a dangerous cycle

The Li Lab

Principal Investigator: Sheng Li, Ph.D.

Our research focus

Open Positions

Selected Publications

Highlighted Abstract

Essential

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