One of the research goals of the Benjamin Kidder lab is to understand how stem cells pattern the epigenetic landscape in a way that facilitates unique expression programs throughout development. Investigating mechanisms of self-renewal and differentiation during mammalian development will ultimately contribute to our understanding of cellular fate decisions. Humans develop from a single fertilized egg into a complex organism with many cell types, each with its own distinct gene expression and epigenetic profile. These complex cellular states, when perturbed, can lead to disease or cancer. My aim is to evaluate epigenetic states that define distinct cell types, investigate mechanisms of reprogramming and transdifferentiation, and develop approaches to transdifferentiate one cell type into another.
Chromatin Modifying Enzymes in Development and Disease
How do chromatin constituents (e.g. histone modifiers/chromatin remodeling proteins) regulate stem cell function and mammalian development? We are particularly interested in understanding how histone modifiers contribute to the diverse cellular repertoire that exists in mammals, and how histone modifiers interact with tissue-specific transcription factors to pattern epigenetic landscapes during development.
We previously demonstrated a critical role for KDM5B (H3K4me3/2 demethylase) in regulating ES cell differentiation (Kidder et al., 2013). We also discovered that KDM5B functions to focus H3K4 methylation at promoters and enhancers (Kidder et al. 2014). Results from these studies also demonstrate that KDM5B (H3K4me3/2/1 demethylase) and LSD1 (H3K4me2/1 and H3K9me2 demethylase) co-regulate H3K4 methylation at active promoters but they retain distinct roles in demethylating gene body regions and bivalent genes (Kidder et al., 2014). One of our goals is to investigate the role of chromatin modifiers, including lysine demethylases and lysine methyltransferases, and chromatin remodeling proteins, in stem cell function, development, cancer, and reprogramming and transdifferentiation.
Genome Stability and Cancer Epigenetics
A central goal of our lab is to understand the role of heterochromatin in regulating genome stability and tumorigenesis. Histones are proteins that bind DNA and facilitate its compaction into chromatin, which is important for regulating gene expression. A densely packed chromatin structure, termed “heterochromatin”, is important for gene silencing during development and is a regulator of genome stability. Alteration of heterochromatin leads to human diseases including cancer and neurological disorders. Decreased levels of H4K20me3, which is found at specific regions of genomic DNA, is a hallmark of human cancers. Our goal is to study the role of a novel H4K20me3 methyltransferase in regulating heterochromatin and cancer formation.
We are interested in understanding how cells acquire unique expression patterns throughout development. Understanding complex transcriptional regulatory circuits requires the generation, analysis, and integration of large-scale datasets. Our lab uses experimental tools and network biology to simplify complex transcriptional systems.
Reprogramming and Transdifferentiation
We are interested in understanding how transcription factors and chromatin modifiers facilitate reprogramming and transdifferentiation. We previously showed that KDM5B and LSD1 are barriers to the reprogramming process (Kidder et al., 2013), and depletion of KDM5B leads to an extension in self-renewal under differentiation conditions (Kidder et al., 2013). Our future goal is to investigate mechanisms of transdifferentiating one cell type into another.
Embryonic Stem Cell Self-Renewal and Differentiation
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