University Chairman, Department of Cell Biology
Professor, Department of Cell Biology
Judith and Burton P. Resnick Professor
Chanin Bldg., Room 402
||Key Words: Leukemia, proliferation, differentiation, chromatin, transcription
Our laboratory is interested in understanding the mechanisms controlling mammalian development and cell differentiation. Our approach is to investigate systems in which these processes are disturbed, either by malignant transformation (leukemia) or by directed gene inactivation in mice and Drosophila. Currently there are three major projects underway in the lab.
Molecular Mechanisms of Leukemia: In this project we are investigating the molecular mechanisms for a block to differentiation present in blood cell tumors (leukemias). We have traced the cause of the differentiation block to a transcription factor called PU.1. We are trying to learn how dysregulation of PU.1 expression causes the leukemia cells to stop differentiating and start proliferating in an uncontrolled manner by studying the effect of PU.1 on other gene products, including, other transcription factors like GATA-1 and co-factors like RB that promote differentiation, and cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors that promote proliferation. This project includes genome-wide approaches involving chromatin immunoprecipitation and high throughput sequencing (ChIP-Seq) and gene expression profiling with microarrays.
Role of H1 Linker Histones and Chromatin Remodeling Factors in Chromatin Structure, DNA Methylation, Gene Expression and Development in Mice and Drosophila. Recent studies show that posttranslational modifications of core histones (H2A, H2B, H3, H4) (the Histone Code) play a very important role in control of gene expression. The H1 linker histones are more diverse than the core histones. Mice contain 8 H1 histone subtypes including differentiation-specific and tissue-specific subtypes, whereas Drosophila has only one type of H1. H1’s are thought to be responsible for the final level of packaging DNA into the compact chromatin structure but we know very little about their role in gene expression and development. We are studying the functional roles of H1 linker histones by inactivating (knocking-out) specific H1 genes in mice and the single H1 in Drosophila. We are also reintroducing mutant H1 linker histones into H1 depleted mouse cells and flies, to perform structure-function studies. We have also established a new connection between H1 histones, DNA methylation and genomic imprinting and we are learning how H1 regulates DNA methylation. We also have a new knock-out mouse for the SNF2H chromatin remolding ATPase, which assembles H1 histone into chromatin.
Human ES Cell Proliferation and Totipotency. Continuous cell proliferation is required to maintain human embryonic stem cell totipotency. We have found that certain central regulators of the cell cycle also control differentiation decisions in the hematopoietic system. We are investigating which cell cycle regulators control human ES cell proliferation and whether these molecules also control their totipotency.