Scientists

Our lab studies the hormonal regulation of behaviorally relevant neuropeptide systems, using the sexually dimorphic and highly steroid responsive vasopressin (AVP) system as a model. As differences in mRNA levels have been linked with epigenetic modifications of DNA (i.e., DNA methylation), we have found that hormonally-induced changes in AVP mRNA levels coincide with transient methylation patterns on the AVP gene. We are interested in further exploring transient epigenetic processes that can have behavioral consequences in adults. 

Our lab studies how early gene x environment interactions epigenetically modify  DNA methylation patterns within the developing brain and have lasting consequences on sex differences in brain physiology and behavior. The candidate genes we focus on are the X-chromosome gene MeCP2 and estrogen receptor alpha., The environmental factors, which we study mainly concern maternal care (i.e. licking and grooming).

Exposure of rat pups to high or low levels of maternal care-giving in the first few days of life can alter the regulation of stress-reactivity and other phenotypic outcomes into adulthood. These changes in behavior accompany changes in gene expression and DNA methylation. As one line of research in the laboratory we are examining the effects of early life maternal care on social behavior, as well as studying experience dependent changes in epigenetic regulation of genes in central and peripheral tissue.

Why does the cell require ~100 or more modifications to maintain two (i.e., open and closed) or a handful of chromatin states?  The histone code hypothesis was formulated to address this problem and “suggested that distinct functional consequences result from histone modifications and that a given outcome is encoded in the precise nature and pattern of mark”.  A number of studies are revealing that histone modifications form a complex, robust regulatory network that controls chromatin and processes that depend on it including transcription and DNA replication.  In my laboratory, we are analyzing histone modification/variant ChIP-Seq data using machine learning methods to uncover this regulatory network.  We are applying our methods to a number of biological systems to characterize the role of epigenetics in metastisis, transcription, DNA replication, aging and sex differences.          

Our studies focus on the cellular mechanisms by which the sex steroid hormones act in the brain to influence behavior, focusing on the ways in which the environment influences those processes.  We made the surprising discovery that when mice are shipped from suppliers during the pubertal period they are hyporesponsive to ovarian hormones much later in adulthood.  This is an enduring effect that can be replicated by an acute immune challenge. A likely explanation for this is that the pubertal stressor alters the transcription of steroid receptors via an epigenetic alteration.

Methylation had broad affects on DNA, DNA structure, and transcription. In my lab we study the molecular mechanisms of methylation and two of our projects interface with the RCN. First, we are working to define the effect of the endocrine disruptor, Bisphenol A, on the epigenome in the developing mouse brain and to relate these changes to behavior and neurodevelopment. Second to quantify epigenetic modulation of genes and demonstrate how this modulation affects human social behavior we are using regional brain activation evoked by well-validated social tasks as an index of social function. 

One well documented sex difference in the brain is the vasopressin innervation which is much more pronounced in male than in female brains. This difference, which we discovered initially in rats, is highly conserved among vertebrates. Most likely, differentiation of vasopressin expression depends on epigenetic changes in a set of existing cells. In addition, recently, we have shown that vasopressin expression is also differentially sensitive to immune stress during development. Exposure to lipopolysaccharides (LPS) during pregnancy reduces vasopressin expression in male but not in female offspring. As vasopressin has been implicated in social behavior, this may explain some of the differential effects that we see of such treatment on social behavior.

The Dutta laboratory discovered that microRNAs miR-206, -1, -424, -503, and -486 are induced during muscle differentiation and promote differentiation by inhibiting several cell-cycle regulators and anti-differentiation transcription factors.  In addition, they are investigating the total pool of short RNAs in cell lines and have discovered (a) that the miR-100 family of microRNAs has a tumor suppressor role in these cells and (b) the existence of a novel class of short RNA, tRNA-derived-RNA- fragments (tRFs) that regulate cell proliferation.

Cellular processes are controlled by complex interactions between components, such as the genome, epigenome, transcriptome and proteome.  My lab uses systems-genetics to dissect processes by reconstructing cellular networks and defining how changes in these networks impact processes, particularly in the process of bone development.  In a recent project we performed a genome-wide screen for genetic variants affecting bone mineralization in the mouse.  Many of the genetic loci identified affected mineralization in a sex-specific manner. 

The work in our lab is centered on understanding the epigenetic mechanism of centromeric chromatin assembly. The centromere is a key regulator of stable chromosomal inheritance and is built upon a nucleosome containing the H3 histone variant CENP-A. We recently identified a histone chaperone for CENP-A, and we are testing whether it is specifically targeted and is the basis for the epigenetic control of centromere location. In addition we are assessing the influence of histone tail modification on the targeting of the CENP-A nucleosome. 

Work in my lab has focused on the mechanisms of sexual differentiation of the central nervous system.  Recently we examined the effects of histone acetylation on sexual differentiation of the brain. Our work shows that a disruption in histone acetylation can block effects of endogenous or exogenous testosterone on sexual differentiation of the brain. 

Post-translational histone modifications generate a localized chromatin environment that regulates chromatin organization and function. Our studies are directed at understanding how conserved histone modifications and the enzymatic complexes that generate them regulate DNA-templated events (such as transcription) and thus cellular function. Such studies have motivated our interest in the epigenetics of brain function, which now includes the determination of sexual dimorphism.

My students and I study heritable variation in the neuroendocrine pathway that regulates fertility in a wild-derived population of field mice. We are interested in the amount of variation that exists within populations, the significance of that variation for fertility and behavior, and the extent to which populations might change over time in response to selection or genetic drift. We study variation in neurons, hormone levels, metabolism, behavior, and morphology. The contribution of epigenetic variation to heritable intrapopulation variation in physiology and function is unknown and potentially important.

In the emerging field of epigenetics that the structure and function of the chromatin template can profoundly affect, how, when and where genes are expressed within an organism. My laboratory’s primary focus is on the post-translational modification of histones, which cause differentiation of neural stem cells. One factor that we would be interested in incorporating into our work is the role of chromosomal sex in these epigenetic processes.

In females, parity induces persistent epigenetic changes in the mammary epithelium that promote genomic surveillance pathways, and prevent abnormal cell division. Conversely, environmental exposures (estrogenic compounds, genotoxins, and cytokines) can reverse these protective epigenetic changes.  In my laboratory chromatin profiling is employed to identify genes that are responsive to hormonal exposures.  Next we will assess if these epigenetic changes can be reversed by environmental exposures.

The adaptive arm of the immune system plays a major role in the functioning of the normal brain and substantially affects cognitive function. My work is centered on the role of the immune system in neuroprotection and function. Because cognitive function and many aspects of the neuroimmune system are epigenetically regulated, we are actively moving into the study of epigenetic effects on the immune system and in turn on the brain function. We are using Rett syndrome as a model to address these and other questions.

The Levine laboratory studies the synthesis, secretion, and actions of gonadotropin-releasing hormone (GnRH), a brain peptide that governs secretion of reproductive hormones from the anterior pituitary gland. In our studies we use a variety of experimental approaches and animal models to ascertain the molecular processes by which gonadal steroids and their receptors differentially program neural systems during development to maintain sex-specific hormone secretory patterns, and hence fertility, in adulthood.  

Females are more vulnerable than males to the reinforcing effects of drugs during the different phases of the addiction process. My laboratory studies biological basis of sex differences in vulnerability to addiction. We have examined a number of biological factors that may underlie these sex differences, and many of our results suggest that epigenetic mechanisms may underlie these sex difference.   

Modern genomic technologies provide unprecedented ability to both widely and deeply interrogate genetic and cellular processes that impact basic science and human health and disease.  However, successful integrative interpretations of large-scale genomic data remains a challenge.  We believe that the analysis of genome-wide profiling experiments is best accomplished as thought-provoking, hypothesis-generating discovery research, from which novel threads of directed research may ensue.  We endeavor to both automate and improve this hypothesis discovery process, developing computational and statistical tools to integrate genome-wide data across genetic, epigenetic, regulatory, genders, expression and signaling components.

Uncovering how complex genomes are epigenetically modified along with identification of the protein and RNA mediators responsible is a critical next step towards understanding the dynamic changes that occur throughout development and differentiation. My interests lie in understanding the epigenetic regulation of mammalian genomes, beginning with the earliest stages of mouse development as a model system.  These key biological processes require global, yet exquisitely precise chromatin remodeling, which set down the bases for sexual dimorphisms in the brain and the body.

The Marler lab studies how the social behavior of adults can be altered by interactions with both the parents during development and adult conspecifics in a territorial and monogamous species of Peromyscus mice.  Our work has shown that aggression, winning behavior and paternal behavior can be altered through environmental manipulations and cause long-lasting behavioral changes.  Changes in androgen receptors and the vasopressin neurochemical pathway are altered in response to the behavioral manipulations. We are interested in studying the epigenetic mechanisms that underlie these behavioral changes. 

fMRI studies have revealed substantial sex differences in cognitive processing and but few studies have examined social perception. Our work seeks to characterize normal and abnormal social function focusing on the brain mechanisms involved in social perception in humans. A new line of research in the laboratory incorporates genomic and epigenetic techniques to help understand individual, and gender, differences in social perception and cognition. 

I examine the steroid-dependent mechanisms through which sexually dimorphic behaviors and brain circuits arise. I also explore the mechanisms by which sexually dimorphic systems and behaviors can be disrupted by environmental estrogens.  We are particularly interested in the mechanisms by which exposure to environmental estrogens can advance puberty and impair fertility in females.  To achieve this, our lab uses an integrative approach combining behavioral biology, neuroanatomy neuroendocrinology and molecular biology.

The discovery of the song system provided the first documentation of sex differences in the vertebrate brain. In 2010, the advent of the complete zebra finch genome assembly has now made questions about epigenetic regulation of song-learning related genes accessible. My lab is currently exploring how the development and differentiation of the song system is regulated by brain-derived steroid production. The addition of an epigenetic approach will therefore likely provide powerful insights into the association between steroid actions and gene expression in the organization of sex differences in songbird brain development and behavior. 

In my laboratory we are examining sex differences from the perspective of sex chromosome genes and steroid hormones interactions. Our candidate sex chromosome genes and steroid hormone receptors both act at the level of histone modification. In addition, we study transgenerational actions of the hypothemethylation, Bisphenol A, and its actions on social behaviors. Thus we are trying to understand how and when these processes act, and when, to elaborate sex differences. 

In our European starling songbird model system, socially appropriate vocal responses to female conspecifics are dictated by environmental experience and sex.  In males and females the acquisition of a nest site leads to long-lasting changes in the brain and behavior.  Only individuals that acquire a nest site sing in response to a female.  We are interested in the extent to which epigenetic mechanisms triggered by experience with a nest site dictate these long lasting changes in socially appropriate vocal behavior and the brain.  

Rewarding aspects of food are regulated by a complex set of neuropeptides and neuromodulators. My laboratory works on the neurobiology of food reward using novel mouse models, in addition to development of conditional knockout for specific subpopulations of neuropeptides, we are employing similar techniques to pinpoint epigenetic modifications involved in food seeking behavior. Our studies will be enriched by extending them into the context of sex differences.

NAD+ biosynthesis pathways are related to metabolism, stress resistance, and gene expression, and have been implicated in promoting longevity in multiple organisms ranging from yeast to mammals. Since the sirtuins deacetylate histones are their primary targets, epigenetic control of gene expression is likely to play a critical role in their biology. We are using yeast molecular genetics to identify novel genes and cellular pathways that function in the regulation of life span and in the extension of life span induced by caloric restriction. A special emphasis is placed on genes involved in the epigenetic regulation gene expression and heterochromatin formation.

The Terasawa lab studies the cellular and molecular mechanisms of puberty onset and pulsatile GnRH neurosecretion. Recently, we have found that DNA demethylation is important for in vitro maturation of primate GnRH neurons, when they exhibit a mature secretory pattern. Because epigenetic factors, such as excessive calorie intake, influence the timing of puberty, currently we are focusing on the study of DNA methylation in the genes known to be involved in puberty onset. 

Research in my laboratory mainly focuses on skeletal muscle adaptations induced by endurance exercise. We have started to address a fundamental question regarding gender-specific epigenetic influences from the maternal environment to the fetal genetic template. Specifically, we are interested in identifying genes that are epigenetically regulated in the offspring due to maternal exercise during pregnancy.