RESEARCH

All cells contain identical genome; however, its expression varies drastically from cell type to cell type. Non-random and compartmentalized distribution of functional components is a hallmark of the nucleus in multicellular organisms. In these organisms, DNA is organized with help of basic proteins into an orderly packaged compact structure called chromatin. Chromatin is compartmentalized into ‘active’ and ‘inactive’ domains that reflect the transcriptional potential of the genomic regions that segregate into them. Out of the thousands of protein-coding ‘genes’ or DNA segments that each cell contains, only a fraction is used at any given time, and those genes that are seldomly used are packaged much tightly as compared to the ones that are ‘expressed’ or used during the lifetime of a cell. Such genes are often ‘transcriptionally poised’, which means they are ready-to-fire as per demand. The higher-order assemblies of chromatin also contribute towards stringent and signal-dependent regulation of gene activity. Moreover, the various hierarchical levels of higher-order chromatin assembly are interconvertible depending upon the physiological status of the cells. Dynamic nature of chromatin loops is one such mechanism wherein the structural transitions lead to functional consequences. Technological advances in recent years have provided unprecedented insights into the role of chromatin organization and interactions of various structural-functional components towards gene regulation.

Studies including those from the Galande laboratory in recent years have unraveled the role of SATB1 in organization of chromatin ‘loopscape’ and its dynamic nature in response to physiological stimuli. Using global chromatin organizer and master regulator SATB1 as a paradigm Dr Galande’s laboratory set out to address the fundamental question of how such compartmentalization of gene activity is coordinated. This is accomplished using the model of development and differentiation of cells of the immune system as well as during tumorigenesis to provide novel insights into the molecular mechanisms of such coordinated gene regulation. Research from our laboratory has also provided insights into how environmental factors ‘epigenetically’ govern gene expression patterns by virtue of key cellular signaling pathways. Recent report from our laboratory has provided unequivocal evidence to establish that SATB1, a novel target of Wnt signaling, reprograms the expression of tumor growth and metastasis associated genes to promote tumorigenesis and functionally overlaps with Wnt signaling during colorectal cancer progression. SATB1 is now considered as an important determinant of prognostic value in multiple cancers and our recent findings have elucidated the molecular basis for the same. The immediate outcome of these studies has potential towards designing effective therapeutics.

Molecular Systems Immunology

Role of SATB1 in T lymphocyte development and differentiation

The processes of T-cell development and differentiation are coordinated by a multitude of signaling processes and transcription factors that impart distinct functional properties on progenitors. We have focused on understanding the role of ‘Special AT-rich binding protein 1’ (SATB1) in T-cell development and differentiation. In mice lacking SATB1 thymocyte development is stalled at double-positive (DP) stage suggesting a critical role for SATB1 in thymocyte development. Recent reports from our laboratory and other groups have demonstrated that SATB1 is known to play an important role in the regulation of Interleukin 5 (IL-5) gene locus in peripheral CD4+ T-cells and thereby regulate T-helper 2 (TH2) differentiation. Moreover, we have identified SATB1 as a novel mediator of Wnt signaling such that it can recruit β-catenin onto its targets. T-lymphocyte development and differentiation is a multi-step process that begins in the thymus and completed in the periphery. The sequential development of thymocytes is dependent on T-cell receptor (TCR) signaling and an array of transcription factors. We are interested in studying the cross-talk between such multiple signaling cascades that are important for T- cell development and differentiation

Regeneration Biology

Epigenetic control of regeneration in Hydra

Hydra belongs to phylum Cnidaria. This is one of the early divergent phyla at the base of eumetazoan phylogenetic tree and share eumetazoan properties like defined body axis, distinct germ layers and cell types such as neurons, epithelio-muscular cells etc. Thus representative models of this phylum, such as Hydra,  provide information about the molecular changes that resulted in eumetazoan innovations. Hydra is known for its tremendous regenerative capacity. Hydra exhibits morphallactic regeneration i.e. regaining missing body parts without involving cell proliferation. This property of  hydra allows us to understand how developmental programs related to body pattern formation are evoked for successful regeneration.

Embryonic development

Epigenetic control of early embryonic development in Zebrafish

We are interested in understanding regulation of cell fate specification and cellular movements during early embryogenesis, especially focused on gastrulation. As the developmental biologist Lewis Wolpert rightly said, "It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life". Our lab focuses on delineating the function of vertebrate lineage-specific chromatin organizers during this important stage of development. This is accomplished by employing genetics, imaging and genome-wide studies to identify novel chromatin organizers and functionally characterize them.

Cancer Biology

Understanding role of SATB family chromatin organizers in tumorigenesis

SATB family chromatin organizers are known to orchestrate chromatin architecture and regulate global gene expression. Recently, these two chromatin organizers have been shown to dynamically regulate colorectal cancer progression. We showed for the first time that SATB1 shares a feedback regulatory network with TCF7L2/β-catenin signaling and is required for Wnt signaling-dependent regulation of β-catenin. Our studies provide unequivocal evidence that SATB1 reprograms the expression of tumor growth- and metastasis-associated genes to promote tumorigenesis and functionally overlaps with Wnt signaling critical for colorectal cancer tumorigenesis. In-depth mechanistic understanding of regulation of SATB1 across colorectal cancer, implicated a need to develop anticancer therapy by targeting SATB1. In this context we are studying the role of statins, which we have shown to specifically target SATB1.

x-Inactivation

Why, When and How of X Chromosome Inactivation?

We are interested in understanding the structural as well as transcriptional regulatory roles of chromatin organization in influencing the establishment of XCI by attempting to address the following broad questions:

  1. What factors govern the chromatin architecture of X undergoing inactivation?

  2. Do these factors influence the kinetics of XCI?

Neuroepigenetics

Epigenetic regulation in adult neurogenesis

Neural stem cells (NSCs) generate new neurons throughout the life of an organism in mammals (adult neurogensis). Adult neurogenesis has been implicated in tissue homeostasis, brain function, and number of psychiatric diseases associated with cognition, aging and depression. Understanding the epigenetic mechanisms underlying adult neurogenesis represents a prerequisite for future therapeutic targeting of adult NSCs for endogenous brain repair. Previously, we have identified specific epigenetic mechanisms underlying tissue homeostasis. Focus of our current research is to investigate the role of epigenetic mechanisms in regulation of adult neurogenesis. Using genome-wide approaches we aim to understand gene regulatory networks during adult neurogenesis. This will be accomplished using multiple model systems including in vitro neural stem cell culture as well as in vivo conditional loss/gain of function in mouse models.

Acknowledgments:  Greg Dsilva and Manu Unni