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We are employing a broad combination of genomic, genetic, biochemical, biophysical, single-cell and embryological approaches in number of cellular and organismal models to investigate functions of the non-coding parts of the genome, understand regulatory mechanisms underlying cellular plasticity and differentiation, investigate how quantitative changes in gene expression dictate differences in human traits, and study craniofacial development, evolution and disease.MECHANISMS OF LONG RANGE GENE REGULATIONCentral to the cell type-specific transcriptional regulation are distal cis-regulatory elements called enhancers, canonically defined as short noncoding DNA sequences that act to drive transcription independent of their relative distance, location or orientation to their cognate promoter. A major area of investigation in our laboratory is focused on general mechanisms of long-range gene regulation by enhancers, which can activate their target genes over tens of even hundreds of kilobases of genomic distances. We are striving to understand how enhancers are activated in response to developmental stimuli, how they communicate with target promoters, what is the dynamics of this process in living cells, and what is the role of chromatin context in priming or restricting enhancer activity. HUMAN NEURAL CREST DEVELOPMENT, DISEASE AND EVOLUTIONOur laboratory uses Cranial Neural Crest Cells (CNCCs) as a paradigm to study how genetic information harbored by regulatory elements is decoded into a diversity of functions, behaviors and morphologies. CNCCs are a transient embryonic cell group which delaminates from the neural tube, migrates long distances and acquires an extraordinarily broad differentiation potential, ultimately giving rise to most of the craniofacial structures and determining their individual and species-speciﬁc variation. Over a third of human congenital malformations is linked to CNCC dysfunction, including over 700 syndromes with craniofacial manifestations. The goal of our ongoing research effort is to understand how variation in gene expression translates into differences in CNCC behavior, leading to the emergence of normal-range and disease-associated morphological diversity in the craniofacial form. This gene expression variation can result both from the trans-regulatory differences, such as those associated with mutations of transcriptional and chromatin regulators in craniofacial syndromes, and from the variation in cis-regulatory sequences like enhancers. To understand both mechanisms of variation and their cell type specificity, we are using human pluripotent stem cell differentiation models that recapitulate induction, migration and differentiation of CNCCs in the dish and facilitate modeling of human neurocristopathies. To study impact of regulatory changes on facial morphology, we are combining these in vitro models with the in vivo work in mice and frogs and, in collaboration with human geneticists and anthropologists, with the morphometric measurements of craniofacial features in human populations. EXPLORING GENOMIC DARK MATTER: TRANSPOSABLE ELEMENTSTransposable element (TE) derived sequences comprise nearly half of the human genome. It is not always appreciated, however, that most TEs that are present in modern humans invaded the ancestral genome at various points of primate evolution, but are typically not shared with more distal mammals such as rodents. Thus, TE derived sequences form a vast reservoir of largely primate-specific sequences from which novel regulatory functions can evolve. We are interested in understanding how TEs may serve as a substrate for evolution of species- and tissue-specific cis-regulatory elements for the host genes, and we are investigating a developmental aspect of transposon regulation.