Epigenetics & Disease

The Baram Lab is focused on the influence of early-life experiences on developing brain circuits and on the underlying plasticity mechanisms that promote health or disease.  They probe these at molecular, cellular, circuit and functional/behavioral levels using viral- and chemo-genetic techniques, in vivo electrophysiology and imaging, and epigenomic and single-cell transcriptomic methodologies.

Current topics include:

• How early-life adversity/stress provokes anhedonia, and the underlying perturbations of the maturation of reward/pleasure circuitry.
• How early-life adversity/stress provokes spatial memory deficits and the transcriptional / epigenomic mechanisms that re-program hippocampal neurons and circuits.
• How prolonged early-life seizures, especially those associated with fever, disrupt the maturation of hippocampal circuits and memory processes.
• Intra-individual methylomics in rodents and humans as predictive biomarkers of early-life adversity-induced cognitive and emotional problems.
• How multiple concurrent acute stresses, such as occur in mass shootings and natural disasters, impact memory processes in males and females.

The Blumberg Lab is broadly interested in the study of gene regulation and intercellular signaling during embryonic development. They study a family of regulatory proteins called nuclear hormone receptors and their ligands. These receptors are all members of the steroid receptor superfamily and are ligand-regulated transcription factors that regulate important events during embryonic development and adult physiology.

Dopamine is a central neuromodulator of the CNS. Dysfunctions of dopaminergic homeostasis leading to either low or high dopamine levels are causally linked to Parkinson’s disease, schizophrenia, addiction and endocrine tumors. Studies conducted at the molecular, cellular and behavioral levels aim to uncover the molecular mechanisms by which dopamine receptor’s signaling controls neuronal functions and behavior. Genetically engineered mice (knock-out mice) constitute the experimental models in which the lab analyzes how altered or abolished expression of dopamine receptors in specific neurons affects physiological responses. A particular interest is devoted to the analysis of dopamine-mediated effects on motor control and addiction to drugs of abuse. These studies are relevant to the understanding of human neurological and neuropsychiatric disorders.

The Downing lab explores new and innovative approaches to cell and tissue engineering. They are particularly interested in understanding how the genome is regulated through non-sequence-based changes to DNA (epigenetics) during healthy tissue development and disease progression. The human genome contains basic instructions required for multicellular life. However, DNA sequence alone tells only part of the story. While all cells within our body have the same genetic makeup, each cell expresses this genetic information differently, which contributes to variations in cellular identity and specific tissue functions. This differential expression is accomplished through epigenetic regulation of genes. The lab’s goal is to develop molecular tools and biomaterials to synthetically regulate the epigenome for better control over cell fate and behavior. Their biomedical interests include heart regeneration, tissue longevity and robustness, the human-material interface, and cancer.

Specific non-coding regulatory DNA elements called enhancers regulate gene transcription during animal development. The Kvon lab investigates transcriptional regulation by enhancers using cutting-edge genomics, genome editing, and transgenic tools. They are particularly interested in studying the role of enhancers in development and evolution and how enhancer malfunction leads to congenital disease.

The La Spada laboratory applies the tools of molecular genetics, neuroscience, and functional genomics to understand the mechanisms of neurodegenerative disease. 

Over the last decade, the lab has begun working on a number of related neurodegenerative disorders, and now have studies focused on amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and Parkinson’s disease.  While these disorders may appear divergent, one key unifying theme has emerged:  The molecular and cellular pathology underlying neurodegenerative disease is inextricably intertwined with homeostatic pathways that decline in function as we age, indicating that a thorough understanding of neurodegeneration cannot be achieved without defining the basic biology of age-dependent dysfunction.  This realization has led the lab to focus on a set of interconnected processes that are fundamentally important for normal neural function and for disease pathogenesis, including transcription, metabolism, and proteostasis.  The lab is thus interested in (macro)autophagy, a process of cellular self-digestion necessary for survival in the face of starvation, but adapted for removal of damaged organelles and proteins in higher organisms, and found to be critically important for CNS homeostasis.  This work seeks to define regulatory processes by which metabolic information dictates protein / organelle quality control activity via input from key nutrient-sensing factors, such as MAP4K3 and mTORC1.

The lab continues to investigate how transcription is regulated in the nervous system and dysregulated in disease, with their most recent work emphasizing single cell analysis.  Complementing these molecular investigations are studies of cell-cell communication, including efforts aimed at understanding skeletal muscle – motor neuron interaction in motor neuron disease and the functional signaling occurring between neurons, astrocytes, and microglia in the CNS.

Another significant emphasis has been on translational research and therapy development, with programs aimed at gene silencing of dominant disease protein expression (as successfully accomplished for SCA7), and focused upon the identification of small molecules intended to boost mitochondrial function, promote proteostasis, or inhibit mTORC1 activation, with lead compounds currently moving towards clinical testing in HD and SCA7.

The Lee Lab studies how transposons, widespread genomic parasites, influence genome function and evolution through epigenetic mechanisms, both in cis along linear chromosomes and in 3D nuclear space. They aim to identify genetic and dietary causes shaping variation in these transposon-mediated epigenetic effects and decipher the consequences on cellular functions that drive genome evolution within and between species.

The Liu Lab engineers specialized genetic systems that go beyond what nature’s genetic systems can do. They are especially interested in creating systems that dramatically accelerate the speed of biomolecular evolution, that reinterpret the genetic code, and that can record transient information as heritable genetic mutations. These systems are applied to the discovery of useful biomolecules, biopolymers, and therapeutics; the study of molecular evolution; cell and developmental biology; and the creation and evolution of synthetic life. The Liu Lab’s research spans the fields of genetic engineering, synthetic biology, chemical biology, cell biology, and directed evolution.

Key questions that guide the Liu Lab’s research include: What does the map between macromolecular sequence and function look like? How are nearly-infinite high dimensional sequence spaces, such as those defining RNA and protein function, productively searched? How does a gene’s evolutionary past shape its future? How does a cell’s past experiences influence its developmental future?

The Marazzi lab is interested in investigating neurodegenerative diseases in children. They study epigenetic and chromatin-mediated control of gene expression in the context of the cellular response to pathogens or differentiation. The lab is interested in mechanisms that control the cell’s response, using biochemistry, genetics, and next generation sequencing techniques to understand molecular mechanisms and genome-wide effects of known and novel candidate genes.

The Mortazavi Lab combines experimental work and computational analysis primarily in hematopoietic, skeletal muscle, and embryonic stem cells in human, mouse and other mammals to understand which regulatory elements are conserved, which elements are not conserved but functional, and which elements regulates what genes using a combination of ChIP-seq, DNA methylation, ATAC-seq and RNA-seq starting from ever low amounts as small as single cells and nuclei when practical.

Genetic disruption of skin development and differentiation is responsible for diseases that affect >20% of the population. The Sun Lab uses primary skin cells, human skin organoids, and xenograft models to decipher the genomic regulators and molecular pathways that govern skin development and disease. The group integrates laboratory and patient-originated approaches. Our current interests include:

• Determining the function of non-protein coding genomic elements in the skin with a focus on non-coding RNAs (ncRNAs).
• Discovering new disease-causing genetic mutations in the coding and non-coding genome and understanding their molecular mechanisms. The lab has a particular interest in subjects with genetic mosaic skin conditions.
• Understanding the genetic and epigenetic impacts of medications on the skin.

The Thompson laboratory has been actively engaged in investigating the fundamental molecular and cellular events that underlie how the mutant Huntington’s disease gene causes degeneration of specific brain cell populations to induce motor and cognitive decline and premature death of patients with the ultimate goal to develop new therapeutic approaches. HD was one of the first neurodegenerative diseases for which a genetic cause was determined, and has served as a paradigm for researchers to study other such diseases. HD is an autosomal dominant neurodegenerative disease characterized by specific regions of neuronal dysfunction and loss, most notably of neurons in the striatum and cortex. The primary cause of HD is the expansion of a CAG triplet repeat encoding a polyglutamine (polyQ) tract within the amino terminal portion of the Huntingtin (Htt) protein. The mutation disrupts many cellular processes, including transcriptional regulation, vesicular trafficking, mitochondrial function, autophagic clearance, and protein modification, among others. The laboratory also focuses on understanding casual mechanisms that underlie Amyotrophic Lateral Sclerosis and more recently, X-linked Dystonia-Parkinsonism with the goal of developing treatment options for the disease. The research benefits from the integrated use of patient iPSCs and mouse models of disease together with the studies of RNA biology and network-based bioinformatics.

The Watanabe Lab’s research focus is centralized around 1) creating powerful organ-on-a-chip systems to improve established brain organoids, 2) developing a brain organoid model for neurodevelopmental disorders, and 3) defining the microcircuit properties of brain organoids as a model system for human brain activities.

The use of a human brain model is ideal in examining and developing therapeutic interventions for neurological disorders such as Autism and Alzheimer’s Disease. To study these human specific diseases within rodent models, as it has traditionally been done, simply may not be practical since such models fail to mimic human symptoms and consequently, the effect of different clinical interventions. Obtaining and using human fetal/adult tissue, however, has proven to be difficult and has introduced a variety of ethical concerns. This problem has been met with the development of brain organoids, which are human pluripotent stem cell (hPSC)-derived 3D structures that express neural activities and circulatory functions that are reminiscent of the actual human brain. Through her former research, Dr. Watanabe has developed innovative and highly efficient methods for constructing these “mini-brains,” thereby allowing them to be utilized in studying the effects of genetic and environmental factors on human brain development and function. The Watanabe Lab currently intends to employ such methodologies for constructing patient-derived brain organoids in order to assess the underlying cause of and potential cures for neurological diseases.

The Yokomori laboratory investigates the mechanisms of chromosome structural organization and how they affect DNA repair and gene regulation in human health and disease. Specifically, they use various DNA damaging methods, including laser microirradiation to study nucleus-wide epigenetic responses to complex DNA damage through PARP signaling and metabolic alteration. The mechanism and function of heterochromatin disruption in FSHD muscular dystrophy is another area of research, in which they perform single cell/nucleus analyses to isolate and characterize a small number of disease-driving cells and are developing 3D and tissue on a chip to measure intrinsic defects of FSHD and CRISPR-engineered mutant myocytes.