Epigenetic Regulation of Microglia in Neurodegenerative Diseases

Johannes Schlachetzki, MD, PhD
Postdoctoral Fellow/Assistant Project Scientist
Department of Cellular and Molecular Medicine 
University of California, San Diego
La Jolla, CA, USA

This conference is part of the the IRCM Early-Career Scientist Seminar Series (ECS3), a groundbreaking initiative whose mission is to showcase early career scientists. This is a great opportunity to discover the exciting projects of these researchers in training in front of a multidisciplinary audience.

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In person : 
IRCM Auditorium
110, avenue des Pins O, H2W 1R7 Montreal

Online :
Zoom link : https://zoom.us/j/95269762104
ID : 952 6976 2104
Code : 476372

IRCM conferences are set to occur under a hybrid format. However, please note that last-minute changes to online-only lectures may occur due to unforeseen circumstances. We invite you to visit this webpage again a few days before attending.

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About this conference : 
My research is aimed at understanding the mechanisms by which genetic and environmental factors modulate the identity of microglia in neurodegenerative diseases such as Alzheimer’s disease (AD). Microglia, the innate immune cells of the brain, are highly plastic cells that interact with their microenvironment and upon detection of neuronal cell death, myelin debris, or amyloid species, adjust their gene expression program to promote a diverse set of immune responses. 
Here, I decipher the epigenetic landscape that drives the gene expression signature of microglia in AD using a multi-omic approach. Specifically, I use ATAC-seq and ChIP-seq to identify changes in chromatin accessibility and active gene regulatory elements of microglia isolated from human postmortem brain tissue and mouse models of AD pathology. 

Bioinformatical analysis showed an enrichment of members of the microphthalmia transcription factor family (Mi/TFE) in gained active gene regulatory regions in amyloid and tau mouse models. The Mi/TFE (MITF, TFEB, TFE3) regulates a wide variety of functions, including autophagy, lipid catabolism, and inflammatory response. By performing transcription factor ChIP-seq for each of the family members, we assessed genome-wide binding of all Mi/TFE transcription factors in microglia as well as neurons and oligodendrocytes. Next, I established culture systems including IPSC-derived microglia-like cells to study the Mi/TFE members in vitro. Lastly, I knocked down Mi/TFE family in wild-type mice by using antisense oligonucleotides to study their effect on microglia gene expression.
Collectively, we demonstrate that the Mi/TFE family drives microglia gene expression in AD.
 

Interview with Dr. Johannes Schlachetzki
Question
Please tell us about your career path, leading up to your application to the Early-Career Scientist Seminar Series

Réponse | Answer 

Réponse | Answer 
“I studied medicine in Rostock and Freiburg, Germany. During medical school, I spent a research year at UCSD, studying the proliferation of myelinating cells in the dorsal root and this first insight into research resulted in sustained enthusiasm to answer more questions related to the brain. I decided to become a neurologist with a focus on neurodegenerative diseases for which there is a lot to discover in terms of pathogenesis and treatment. During my residency, I became interested in microglia and their role in neurodegeneration. In 2015 I decided to join the laboratory of Chris Glass at UCSD to understand how microglia “think” in the context of neurodegenerative diseases using next-generation sequencing technologies.” 

Question
Please tell us about your passion for research. What motivates you most about your work?

Réponse | Answer 
“During my pre-clinical studies, my anatomy professor at the University of Rostock sparked my interest in neurosciences and I was fascinated by how plastic and complex the brain is. At that time, not much progress has been made in understanding the pathogenesis of neurodegenerative diseases, hence the lack of potential disease-modifying treatments. In contrast, over the last two decades, new treatment options have entered the clinic for other neurological conditions, including neuroimmunological diseases and monogenic diseases such as multiple sclerosis and spinal muscular atrophy, respectively. By increasing the fundamental knowledge about how the brain functions and what goes wrong in disease, we may develop new therapeutic avenues for diseases like Alzheimer’s disease. The progress we make in understanding the pathogenesis of neurological diseases and in parallel the rapid advancement of technologies is fascinating and motivates me every day.”

Question
Please tell us about your professional goals. What do you hope to accomplish as a scientist?

Réponse | Answer 
“I hope to contribute to providing more insight into the function of microglia and their role in neurodegeneration. One goal is to use microglia as therapeutical vehicles for the treatment of neurodegenerative diseases. Beyond scientific accomplishments, I hope to spark enthusiasm in young students to work on scientific questions and to be part of the journey to find solutions to difficult questions related to neurological diseases.”