Massively parallel functional dissection of schizophrenia-associated noncoding genetic variants.

Schizophrenia (SCZ) is a highly heritable mental disorder with thousands of associated genetic variants located mostly in the noncoding space of the genome. Translating these associations into insights regarding the underlying pathomechanisms has been challenging because the causal variants, their mechanisms of action, and their target genes remain largely unknown. We implemented a massively parallel variant annotation pipeline (MVAP) to perform SCZ variant-to-function mapping at scale in disease-relevant neural cell types.

MDM2 Influences ACE2 Stability and SARS-CoV-2 Uptake.

Angiotensin-converting enzyme 2 (ACE2) is the central entry receptor for SARS-CoV-2. However, surprisingly little is known about the effects of host regulators on ACE2 localization, expression, and the associated influence on SARS-CoV-2 infection. Here we identify that ACE2 expression levels are regulated by the E3 ligase MDM2 and that MDM2 levels indirectly influence infection with SARS-CoV-2.

Cell type and condition specific functional annotation of schizophrenia associated non-coding genetic variants.

Schizophrenia (SCZ) is a highly polygenic disease and genome wide association studies have identified thousands of genetic variants that are statistically associated with this psychiatric disorder. However, our ability to translate these associations into insights on the disease mechanisms has been challenging since the causal genetic variants, their molecular function and their target genes remain largely unknown. In order to address these questions, we established a functional genomics pipeline in combination with induced pluripotent stem cell technology to functionally characterize ~35,000 non-coding genetic variants associated with schizophrenia along with their target genes.

Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology.

The somatic DNA methylation (DNAme) landscape is established early in development but remains highly dynamic within focal regions that overlap with gene regulatory elements. The significance of these dynamic changes, particularly in the central nervous system, remains unresolved. Here, we utilize a powerful human embryonic stem cell differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novo DNAme machinery.