Broadly, our research is focused on understanding molecular mechanisms that regulate cell type-specific gene expression during mammalian development, normal physiological processes and pathological conditions. Although cells of a multicellular organism are genetically homogenous, due to differential gene expression pattern they are different structurally and functionally. During the course of development tissue-specific gene expression arise due to activity of specific transcription factors, changes in chromatin organization and also by RNA interferences. In our laboratory, we use multidisciplinary approaches to understand involvement of these mechanisms during cell lineage commitment (during development) and how alteration of tissue-specific gene expression mechanisms leads to pathological conditions. Areas of major interest include:

1. Transcriptional Mechanisms of endothelial cell development and function:

Defective vasculature in Vegfr1 embryosA major goal of our laboratory is to dissect mechanisms to understand the molecular regulation of blood vessel formation (Vasculogenesis and Angiogenesis) and vascular cell (Endothelial cell) specification and function. Angiogenesis is a key event in many physiological processes, like organ growth and development, wound healing and reproduction, and is also critical for certain pathological disorders including tumor growth/metastasis. Thus, defining such mechanisms has enormous importance regarding vascular tissue engineering and promotion of endogenous regeneration as well as developing anti-angiogenic therapy against pathological angiogenesis. Therefore, to begin to dissect regulatory mechanisms of blood vessel formation, we are defining the transcriptional regulation of key genes including vascular endothelial growth factor receptors (VEGFRs) during early vascular development and adult angiogenesis.

Recent Publications related to this project:
Dutta, D, Ray, S, Vivian, JL, and Paul, S. (2008) Activation of the VEGFR1 chromatin domain: An angiogenic signal-ETS1/HIF-2alpha regulatory axis. J. Biol. Chem. 283:25404-25413.

Dutta, D, Ray, S, Home, P, Wang, S, Sheibani, N, Tawfik, O, Cheng, N, and Paul, S. Regulation of Angiogenesis by Histone Chaperone HIRA-Mediated Incorporation of Lysine 56-Acetylated Histone H3 at Chromatin Domains of Endothelial Genes. (Manuscript under review)

2. Molecular Control of Cell Fate Decision During Early Mammalian Development:

Defective morula to blastocyst transitionThe first lineage decision during mammalian development is the establishment of trophectoderm (TE) and inner cell mass (ICM) lineages. TE contains trophoblast stem (TS) cells. During development, TS cells give rise to differentiated trophoblast cell subtypes that develop into parts of the placenta. On the other hand, embryonic stem (ES) cells can be derived from ICM, which develops into embryonic and some extra-embryonic structures. Current studies in the lab are investigating the role of GATA family of transcription factors during early lineage specification, specifically on the development of Trophectoderm (TE) lineage.

Recent Publications related to this project:
Home, P, Ray, S, Dutta, D, Bronshteyn, I, Larson, M, and Paul, S. (2009) GATA3 is selectively expressed in the trophectoderm of peri-implantation embryo and directly regulates CDX2 gene expression. J. Biol. Chem.284: 28729-37

Ray, S, Dutta, D, Rumi, M, Canham, L, Soares, MJ, and Paul, S. (2009) Context-dependent function of regulatory elements and switch in chromatin occupancy between GATA3 and GATA2 regulate Gata2 trasncription during trophoblast differentiation. J. Biol. Chem. 284:4978-4988

3. Signaling Pathways Regulating Stem Cell Pluripotency:

Oct4 and Nanog expression in undifferentiated mouse ES cellsIn the second project related to this area, we found that inhibition of protein kinase C signaling maintains embryonic stem cell pluripotency. We are now asking down stream molecular mechanisms by which PKC signaling is dictating ES cell differentiation vs. pluripotency.

Recent Publications related to this project:

Dutta, D, Ray, S, Home, P, Larson, M, Shen, X, Orkin, SH, and Paul, S. Self Renewal vs. Lineage Commitment of Embryonic Stem Cells: Protein Kinase C Signaling Shifts the Balance. (Manuscript under review)

Last modified: Jan 02, 2013