Genomics in the News

The molecular and cellular basis of cognitive deficits in schizophrenia remains poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically. Towards this goal, CGM Investigator Steve Haggarty and colleagues studied the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. Profiling GIT1 knockout mice revealed memory deficits and reduced cortical dendritic spine density. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion perturbs specific networks of synaptic proteins, suggesting that GIT1 regulates the phosphorylation of critical regulators of neuroplasticity.

The Karmacharya lab interrogated neurodevelopmental effects of exposure to interleukin-6 (IL-6) and interferon-γ (IFN-γ) in differentiating human cortical neurons. Transcriptomic analyses showed IL-6 exposure affected genes regulating extracellular matrix, actin cytoskeleton and TGF-β signaling while IFN-γ exposure impacted genes regulating antigen processing, major histocompatibility complex and endoplasmic reticulum biology. IL-6 altered mitochondrial respiration in the differentiated neurons while IFN-γ induced reduction in dendritic spine density. Pretreatment with folic acid ameliorated IL-6 effects on mitochondrial respiration and IFN-γ effects on dendritic spine density. These findings suggest cellular processes that mediate maternal immune activation in developing brains and how folic acid mitigates such risk.

This study makes a very important statement about assumptions that have been made regarding what is “good for you” in aging. In this study led by CGM Investigator Alex Soukas and CGM and MGH Endocrine Instructor Armen Yerevanian, the authors show that reducing levels of an essential vitamin, riboflavin, which is necessary to make the cofactor FAD, is beneficial in aging, prompting stress defenses and promoting lifespan extension in C. elegans. While there is a ways to go to prove benefits in humans, it challenges the “dogma” that with vitamins more is better for you.

The length of a CCCTCT repeat within the SINE-VNTR-Alu retrotransposon associated with X-linked dystonia-parkinsonism (XDP) is inversely correlated with the age of disease onset. Here, the Wheeler lab investigated the instability of this repeat. Findings reveal:1) length-dependent and expansion-biased instability, with greater expansions in brain than in blood; 2) brain region-specific patterns of expansion that are broadly similar to those of the Huntington’s disease CAG repeat; 3) evidence that CCCTCT expansion propensity may be modified by local chromatin structure. The data support a role for CCCTCT somatic expansion underlying the rate of XDP onset.