Research

We aim to discover the molecular and circuit bases and develop novel and molecular therapies for human neurodevelopmental disorders caused by genetic or epigenetic defects. Here are the highlights of several ongoing projects in the lab.

ASD is a group of neurodevelopmental conditions that affects more than 1/50 children in US. However, little is known about the pathophysiology underlying unique autism behaviors. SHANK family proteins (SHANK1, SHANK2, & SHANK3) have emerged as promising candidates for modeling ASD in mice due to strong genetic evidence showing reproducible genetic mutations of SHANK family genes in ~2% of patients with ASD. We have generated and characterized both isoform specific and complete Shank2 and Shank3 mutant mice. These mutant mice have the best molecular construct validity for common human genetic defects in human ASD and robust face validity of behavioral phenotypes. At circuit level, we are now interested in understanding the specific circuit defect at cellular level underlying autism-like behavior using cellular tool, retrograde tracing, optogenetic, and in vivo recording in free moving animals. At molecular level, we are interested in studying the molecular change at synapses that could lead to the targeted molecular treatment.

Recent genomics studies have led to the discovery of rare but highly penetrant and reproducible mutations in ~100 genes in individuals with ASD. Surprisingly but not unexpectedly, about 60 genes are classified as epigenetic and transcriptional regulators. Specially, many of these genes encode genes in proteins in basic epigenetic machinery. We reported the first ASD case with mutation in H1-4 (HIST1H1E) gene that encodes a H1.4 linker histone (H1-4).. However, almost nothing is known how deficiency of histone H1 linker could result in very select ASD and intellectual disability (ID). We will model H1-4 causing neurodevelopmental defects using human H1-4 patient derived iPSC and brain organoid as well as mutant mice and uncover new biological mechanism underlying neurodevelopment.

Prader-Willi and Angelman syndrome are two prime examples of genomic imprinting disorders involving the paternal and maternal deficiency of human chromosome of 15q11-q13. The critical gene responsible for the PWS is the small nucleolar RNA SNORD116, that is exclusively expressed from the paternal chromosome. The gene for AS is brain-specific maternally expressed gene UBE3A. Although the molecular bases for both PWS and AS are known for more than a decade, little advance has been achieved to treat these patients in clinic. We are interested in developing molecular and epigenetic therapies using CRISPR/Cas9 epigenome editing or pharmacological manipulation to target the epigenetic modifications in patient derived IPSC and mouse models.

Many rare genetic diseases in clinic remain undiagnosed. We are partially interested in discovering the molecular basis of patients with unusually clinical presentations of neurodevelopmental and neurobehavioral disorders. We will employ the whole genome sequencing approach to uncover the novel candidate gene and then perform functional studies using patient derived cells and mutant mice to understand the molecular basis and ultimately to develop novel treatments: from the bedside to bench and then from bench to bedside.