Functional non-coding genome in synthetic genomes

Most efforts to understand genes in health and disease over the last decades have focused on protein-coding transcripts, which comprise just 2% of the human genome. Given that the number of protein-coding genes in lower and higher organisms are comparable, the huge differences in genome sizes are due to non-coding parts. As a result, the non-coding genome is very likely to contribute to the complex activities and diseases present in higher organisms. We are aiming to better identify and characterize the functional non-coding genome by designing, engineering and synthesizing genomic pieces. Further understanding the function and mechanisms of non-coding regulatory elements will also help better re-design synthetic genomes.

lncRNA mechanisms in diseases

Recent discoveries reveal that the vast majority of the genome is transcribed to generate tens of thousands of long noncoding RNAs (lncRNAs). However, deciphering the molecular function of lncRNAs is challenging. Unlike mRNAs, there is currently no simple way to predict lncRNA activity based on sequence. Initial studies of individual lncRNAs have shown important roles in epigenetic regulation and powerful biological functions, but almost nothing is known about lncRNA function in neural specification or human disease pathogenesis. Based on the overall hypothesis that lncRNAs play important roles in normal brain function and disease conditions, I aim to systematically decipher the roles of lncRNAs in neural differentiation and breast cancer. This will provide comprehensive references, new mechanisms and novel therapeutic targets for neurodevelopmental disorders and breast cancer.

non-coding elements & stem cell fate

Our previous discoveries demonstrated a phenomenon where mutant adult male stem cells switch to female stem cells and cause tumor phenotypes. It is the first evidence that adult stem cells are capable of changing sexual identity. As many disease-associated risk loci reside in non-coding genomic regions, we found that the stem cell conversion phenotype is also caused by non-coding mutations affecting gene expression of a transcription factor. This is of enormous interest since similar defects may trigger testicular cancer or sexual development disorders in humans. We will explore how non-coding mutations contribute to dramatic stem cell sex conversion phenotypes by regulating gene expression in specific cells at different developmental stages.

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