Arthur Skoultchi, PhD

Professor & Chair,     Department of Cell Biology Chanin Bldg., Room 402 718 430-2169 skoultch@aecom.yu.edu Biosketch Complete list of publications Laboratory Home Page

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. Currently there are three major projects underway in the lab. Molecular Mechanisms of Leukemogenesis: In this project we are investigating the molecular mechanisms for a block to differentiation present in tumors of the red blood cell lineage (erythroleukemia). We have traced the cause of the differentiation block in erythroleukemia to the activation of a transcription factor called PU.1 that is normally expressed only in white blood cells. We are trying to learn how activation of PU.1 causes the erythroleukemia cells to stop differentiating and start proliferating in an uncontrolled manner by: (1) studying the effect of PU.1 on other gene products, including Rb, cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors that regulate cell proliferation, and (2) studying the effect of PU.1 on gene products required for promoting red blood cell differentiation. This project includes approaches using techniques of chromatin immunoprecipitation (ChIP) and microarrays. Role of H1 Linker Histones in Chromatin Structure, Gene Expression and Development. Recent studies show that posttranslational modifications of core histones (H2A, H2B, H3, H4) play a very important role in control of gene expression. The H1 linker histones are more diverse than the core histones and consist of 8 subtypes including differentiation-specific and tissue-specific subtypes. 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 have begun to assess the functional roles of H1 linker histones by inactivating (knocking-out) specific H1 genes in mice. We also have derived knock-out ES cell lines and we are developing methods for reintroducing mutant H1 linker histones into these cells, to perform structure-function studies. Our recent work (Cell, 2005) demonstrates a new link between H1 and DNA methylation. 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.

Recent publications Michael Papetti and Arthur I. Skoultchi. Reprogramming Leukemia Cells to Terminal Differentiation and Growth Arrest by RNA Interference of PU.1 Molecular Cancer Research 5, 1053-1062, October 1, 2007. doi: 10.1158/1541-7786.MCR-07-0145. Murga M, Jaco I, Fan Y, Soria R, Martinez-Pastor B, Cuadrado M, Yang SM, Blasco MA, Skoultchi AI, Fernandez-Capetillo O. Global chromatin compaction limits the strength of the DNA damage response. J Cell Biol. 2007 Sep 24;178(7):1101-8. Woodcock, C.L., A.I. Skoultchi and Y. Fan (2006). Role of linker histone in chromatin structure and function: H1 stoichiometry and nucleosome repeat length. Chromosome Res 14:17-25. Fan, Y., T. Nikitina, J. Zhao, T. Fleury, R. Bhattacharyya, E. Bouhassira, A. Stein, C. Woodcock and A.I. Skoultchi (2005). “Depletion of histone H1 in mammals alters global chromatin structure but causes specific changes in gene regulation.? Cell 123(7): 1199-1212 Stopka, T., D. Amanatullah, M. Papetti and A.I. Skoultchi (2005). “PU.1 inhibits the erythroid program by binding to GATA-1 on DNA and creating a repressive chromatin structure.?nbsp; Embo J., 24(21): 3712-23 Fan Y. and Skoultchi AI. (2004) Genetic Analysis of H1 Linker Histone Subtypes And Their Functions In Mice. Methods Enzymol. 377:85-107. . Choe K.S., F. Radparvar, et al. (2003). “Reversal of tumorigenicity and the block to differentiation in erythroleukemia cells by GATA-1. Cancer Res 63(19): 6363-9 Rekhtman N., K.S. Choe, et al. (2003) “PU.1 and pRB interact and cooperate to repress GATA-1 and block erythroid differentiation. Mol Cell Biol. 23(21): 7460-74 Matushansky, I., F. Radparvar and A. Skoultchi. (2003). CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells.  Oncogene, 22:4143-9.    Konishi A., S. Shimizu, et al. (2003) “Involvement of histone H1.2 in apoptosis induced by DNA double-strand breaks.Cell 114(6): 673-88 Fan, Y., et al., (2003). H1 linker histones are essential for mouse development and affect nucleosome spacing in vivo. Mol. Cell. Bio., 23:4559-72.  Stopka, T. and A.I. Skoultchi (2003) “The ISWI ATPase Snf2h is required for early mouse development. Proc Natl Acad Sci USA 100(24): 14097-102  Zhu L, Skoultchi AI. (2001) Coordinating cell proliferation and differentiation. Curr Opin Genet Dev 2001 Feb;11(1):91-7

Arthur Skoultchi: Research interests | Biosketch Faculty research at a glance Birshtein | Bouhassira | Edelmann | Fyodorov | Keogh | Kielian | Kitsis | Nathenson | Query Scharff | Schildkraut | Shafritz | Singer | Skoultchi | Stanley | Steidl |Warner | Ye   Home