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Overview of research interests:

My broad interests lie at the intersection of genetics, genomics and neuroscience. My current research focuses on the interplay between genetic, epigenetic and environmental causes in controlling brain gene expression and behavior in Alcohol Use Disorder (AUD). My lab studies chromatin (epigenomic) and gene expression (transcriptomic) profiles in brain cells and tissues using next generation sequencing and applies systems approaches to data analysis to provide an integrated view of brain changes associated with AUD-related neuroplasticity and neuropathology. An important component of this effort is discovering and prioritizing molecular targets for medication development to prevent and/or treat AUD and other CNS disorders. My collaborators and I validate functional significance of the most promising targets using a combination of approaches that include reverse genetics, behavioral pharmacology, and drug repurposing.

Molecular mechanisms of cellular plasticity in models of AUD.

One goal of these studies is to understand how large-scale molecular signals are integrated to impact cellular functions and downstream alcohol-related behaviors. A second goal is to identify and prioritize alcohol-related molecular targets for medication development for AUD. To accomplish these goals, my lab uses genome-wide molecular profiles (e.g. RNA-Seq and ATAC-Seq) and tools of systems biology, such as gene networks and knowledge bases and develops strategies for data integration within and across genomic data sets, which enables a holistic view of brain responses to perturbations, such as alcohol. For example, we pioneered the usage of gene co-expression network analysis in the alcohol field to study coordinated molecular responses to alcohol in animal models [1] and postmortem human brain [2]. In this 2012 study, we used gene co-expression networks and a novel integration strategy to characterize gene expression changes in alcoholic brain at a systems level. This integrative analysis of the transcriptome allowed us to make mechanistic predictions about the upstream epigenetic control as well as downstream cellular physiology and we validated several of these predictions experimentally. 

The 2012 study established a foundation for my current and future research on the role of epigenetic (epigenomic) mechanisms in AUD. We extended this work in two important directions: 1) epigenetic control of alcohol-related gene expression in human postmortem brain and 2) the effects of epigenetic drugs on alcohol-related behaviors in animal models. The premise of this line of research is that epigenomic states represent long-lasting attributes of cellular identity, including patterns of past gene expression, current gene expression, and potential experience-dependent responses, which, in the context of AUD, may explain how chronic alcohol establishes persistent changes in brain plasticity underlying compulsive drug use, craving, and relapse.

Studying cell type – specific molecular profiles is critical for understanding the roles of individual neuronal and glial populations in CNS plasticity and pathology. My lab was among the first to combine gene expression profiles from complex brain tissues with cell type – specific transcriptomes from publications and online databases, such as Allen Brain Atlas (), to define cellular identity of transcripts changed by perturbations. These analyses helped generate focused hypotheses about the role of specific cell types in drug-, mutation- or stress-induced perturbations [2, 3, 4]. Recently, my lab utilized two novel procedures (INTACT and ATAC-Seq) to obtain epigenomic profiles from specific neuronal populations and we are currently using these approaches to study cell type-specific epigenetic mechanisms in AUD models.

Another line of research in my lab is the role of neuroimmune signaling in promoting excessive alcohol drinking and transitioning to alcohol abuse and AUD. Our early studies implicated the neuroimmune signaling in regulation of alcohol consumption. Follow-up studies corroborated this finding, showing that effects of alcohol are associated with immune activation and pro-inflammatory signaling [2]. Genetic deletion (knockout) of some of the immune genes nominated by gene expression studies reduced ethanol consumption and preference and provided behavioral validation for genomic experiments [5]. Furthermore, administration of small pro-inflammatory molecules, such as LPS and Poly(I:C) increase ethanol consumption in mice, indicating that enhancement of immune signaling is associated with increased drinking as suggested in humans. We lack understanding of how changes in neuroimmune pathways are integrated into neuronal networks that mediate the transition from normal (social) drinking to excessive alcohol consumption. We are currently conducting experiments (supported by NIH, R01) to address this question. The results of these studies will advance our understanding of the role of neuroimmune signaling in the transition to AUD and will be widely applicable to brain disorders with pro-inflammatory phenotypes

Selected References
1. Mulligan MK, Rhodes JS, Crabbe JC, Mayfield RD, Harris RA and Ponomarev I (2011) Molecular profiles of drinking alcohol to intoxication in C57BL/6J mice. Alcoholism: Clinical & Experimental Research, 35:659-670.
2. Ponomarev I, Wang S, Zhang L, Harris RA and Mayfield RD (2012) Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. The Journal of Neuroscience, 32:1884-1897.
3. Ponomarev I, Maiya R, Harnett MT, Schafer GL, Ryabinin AE, Blednov YA, Morikawa H, Boehm II SL, Homanics GE, Berman A, Lodowski KH, Bergeson SE and Harris RA (2006). Transcriptional signatures of cellular plasticity in mice lacking the alpha 1 subunit of GABAA receptors. The Journal of Neuroscience, 26:5673-5683.
4. Ponomarev I, Rau V, Eger 2nd EI, Harris RA and Fanselow MS (2010) Amygdala transcriptome and cellular mechanisms underlying stress-enhanced fear learning in a rat model of posttraumatic stress disorder. Neuropsychopharmacology, 35:1402-1411.
5. Blednov YA, Ponomarev I, Geil C, Bergeson S, Koob GF and Harris RA (2012) Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies. Addiction Biology, 17:108-120.