About Us
A molecular neuroscience lab, we study how genes control of the development and function of the mammalian brain. We are especially interested in the application of unbiased omics methods to identify pathogenically relevant molecular interactions in genetic mouse models of neurologic disease. After identifying pathogenic mediators, we characterize their function through an array of targeted methods tat range from behavior to microscopy and biochemistry. In this effort, we closely collaborate with labs within UCSD and at other institutions to perform genetic, bioinformatic, proteomic and structural biology experiments.
Dr. Ferguson is member of the Neurosciences graduate program as well as the Biomedical Sciences graduate program (Cell & Developmental Biology and Genetics & Genomics). We are looking to recruit curious, motivated graduate students and post-doctoral fellows. Interested individuals should email Dr. Ferguson at cferguson@health.ucsd.edu.
Projects
Ubiquitin in chromatin regulation by the Polycomb Repressor Complex (PRC1) in the brain. Polycomb repressor complexes play diverse and fundamental roles in chromatin regulation, however their functions in the brain have been explored to a limited degree, despite linkages to neurologic disease. We found that the PRC1 product ubiquitinated histone H2A (H2A119ub) is remarkably dynamic during neurodevelopment, undergoing enrichment within euchromatin especially active enhancers. To probe the neuronal functions of histone ubiquitination, we generated brain-specific mutants in Bap1 (Brca1-associated protein), which erases H2AK119ub. We are now applying a combination of next-generation sequencing methods (CUT&RUN, RNA-seq, micro-C, Hi-C and Hi-ChIP) to understand the function of PRC-dependent chromatin modifications on gene regulation in the brain.
Regulation of heterochromatin by ubiquitin-mediated protein degradation. We previously identified key targets of the ubiquitin ligase Anaphase-Promoting Complex in differentiating neurons, in particular Ki-67 and the Chromosome Passenger Complex (CPC). Consisting of INCENP, Aurora B, Survivin and Borealin, the CPC regulates histone phosphorylation (H3S10ph) within constitutive heterochromatin in differentiating neurons. Remarkably, we were able to correct heterochromatin dysregulation in vivo in the brain by administering small molecule inhibitors of Aurora B. We are now examining the role of histone phosphorylation in heterochromatin formation in post-mitotic neurons through a combination of in vitro and in vivo assays.
Regulation of phase separation in neuronal heterochromatin by Ki-67. A major substrate of the APC in neurons which we identified in mouse models of the ANAPC7 neurodevelopmental syndrome (OMIM 619699, Ferguson-Bonni disorder), Ki-67 is a massive and highly disordered protein. During mitosis, Ki-67 organizes the chromosome periphery, whereas after mitotic exit Ki-67 contributes to the formation of heterochromatin, but how it accomplishes this feat is poorly understood. We have generated mouse models of Ki-67 deficiency in the brain and are currently exploring how Ki-67 loss impacts neuronal development through a combination of microscopy, genomics and behavior assays as well as minimally reconstituted in vitro chromatin assays.
Role of Fig4 in neurodegeneration. Fig4, along with Vac14 and PIKfyve/Fab1, comprise the biosynthetic complex which regulates the lysosomal signaling lipid PI(3,5)P2. Mutations in Fig4 cause amyotrophic lateral sclerosis (ALS, LouGehrig’s disease) and a fatal form of Charcot-Marie-Tooth disease CMT4J. We carried out the first comprehensive interrogation of proteinopathy in the brain of Fig4 mutant mice, which revealed pathogenic connections to Alzheimer and Parkinson diseases, while also identifying molecular mediators of inflammatory cell death. We are now employing cell-specific mouse models to characterize the interactions between neurons, astroglia and microglia using a combination of proteomics, imaging and transcriptomic analyses.
Methods
Ferguson Lab UCSD
Leichtag Family Biomedical Research Building, 9500 Gilman Dr, La Jolla, California 92093, United States
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