Epigenomics and Epitranscriptomics

Histone H3K9me2 chromatin patterning arises "de novo" in committed cells

Epigenomics generally refers to regulatory features of the genome that can be passed from one generation to another -- either from mother to daughter cells or from parent to child -- without altering the actual DNA coding sequences of genes. The epigenentic regulatory features most commonly studied are chemical modifications of DNA (such as methylation) or histone proteins (the proteins that help pack down chromosomal DNA in the nucleus). From our published studies, we have examined roles for histone function during ESC exist from the pluripotent state (Schaniel et al., Stem Cells 2009) and roles for particular histone marks (e.g., H3K9me2) during hematopoietic stem/progenitor cells lineage commitment (Chen et al., 2012 Genes and Dev.). From our hematopoietic stem cell (HSC) studies, HSCs are developmentally "reprogrammed" to have little or no histone H3 lysine 9 methylation in the primitive state. Upon lineage commitment, H3K9me2 marks are nucleated at specific sites in the genome and then spread across the entire genome (Chen et al., 2012 Genes and Dev.). Increase in this mark coincides with global changes in chromatin structure during differentiation (Schones et al., Epigenetics and Chromatin 2014). One possibility is that the absence of this histone mark promotes developmental plasticity in uncommitted stem and progenitor populations.

Epitranscriptomics generally pertains to chemical modifications of mRNA occurring during or after gene transcription. We are currently performing broad genomic surveys of the impact of mRNA methylation (i.e., N6-methyladenosine) on regulation of key gene mRNAs required for progenitor cell lineage commitment and stem cell self-renewal (Kuppers et al., in preparation).

Nanog-GFP expressing mouse ESC colony (from Schaniel et al., 2006/2009

There are over 200 different cell types in the human body, each with a specialized function, which arise during development and adult tissue homeostasis from transient or established progenitor cells resident in tissues and organs. Two emerging themes in disease research emphasize why it is crucial that we understand how cell identities are formed and maintained in mammals. First is the notion that cancer cells may arise from maligned development programs. In addition to co-opting growth and survival promoting pathways, tumor cells hijack molecular pathways that are normally involved in developmental processes such as cell fate determination. The existence of cancer stem cells, which may play vital roles in tumor progression, maintenance, and recurrence, underscores this notion. Second is the notion that, with the successful isolation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), we can develop techniques to harness their developmental potential in the laboratory for clinical applications, such as cell replacement therapies for neurodegeneration, spinal cord injury, liver dysfunction, severe burns, blood disorders, etc. Through the use of defined, in vitro embryonic and somatic stem cell systems, we will find and characterize gene products affecting stem cell self-renewal, differentiation, proliferation, and survival.

To date we have examined several aspects of regulation of cell identify and cell growth:

How mouse embryonic stem cells exit the pluripotent "ground" state (Schaniel et al., Nature Methods 2008; Schaniel et al., Stem Cells 2009; Betschinger et al., Cell 2013).

How human embryonic stem cells exit the pluripotent "ground" state (Mathieu et al., in preparation w/ Dr. Hannele Ruohola-Baker's group).

How human hematopoietic stem cell exit the multipotent state (Chen et al., Genes and Dev. 2012).

How hematopoietic progenitors commit to the erythroid lineage (Kuppers et al., in preparation).

How cells regulate the G0-quiescent-like state during cell cycle progression (Feldman et al., in preparation).