Regulation of Cellular Differentiation

Overview

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Murine hematopoietic hierarchy with cell surface marker based subfractioning of the multipotent stem and progenitor compartment.

The epigenetic landscape dynamically changes with differentiation and coordinated programming of epigenetic marks guarantees faithful differentiation. Disturbances of these epigenetic patterns predispose to disease. Our group investigates the epigenetic mechanisms that control normal and malignant hematopoietic differentiation. To this end, we employ state-of-the-art omics techniques (e.g. tagmentation-based whole genome bisulfite sequencing, ChIP-seq, RNA-seq) to determine epigenetic patterns and their dynamics as well as their effects on the transcriptomes in hematopoietic tissues and in leukemia. Furthermore, we are investigating the functional and epigenetic consequences of dysregulated expression of epigenetic modulators using several in vivo models.  

We believe that understanding the (epigenetic) regulation of normal hematopoiesis is key to understand the process of leukemogenesis. Thus we anticipate, that our research will not only have a direct impact on our understanding of leukemia biology but it will also enable us to develop novel treatment strategies for human leukemias which interfere with aberrant pathway activation to counteract dysregulated epigenetic processes.

 

Major Research Directions

  • Identification and functional characterization of epigenetic mechanisms regulating hematopoiesis
  • Functional studies on consequences of deregulated epigenetic patterns
  • Understanding lineage bias in the multipotent progenitor cell compartment
  • Identification and functional validation of cis-regulatory elements in hematopoiesis

 

Selected Recent Publications

Wilhelm T*, Lipka DB*, Witte T*, Wierzbinska JA, Fluhr S, Helf M, Mücke O, Claus R, Konermann C, Nöllke P, Niemeyer C, Flotho C, Plass C. Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia. Epigenetics 2016 (in press)(* Co-first author)

Oakes CC, Seifert M, Assenov Y, Gu L, Przekopowitz M, Ruppert AS, Wang Q, Imbusch CD, Serva A, Koser SD, Brocks D, Lipka DB, Bogatyrova O, Weichenhan D, Brors B, Rassenti L, Kipps TJ, Mertens D, Zapatka M, Lichter P, Dohner H, Kuppers R, Zenz T, Stilgenbauer S, Byrd JC, Plass C. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet 2016 (in press)

Schnöder TM, Arreba-Tutusaus P, Griehl I, Bullinger L, Buschbeck M, Lane SW, Döhner K, Plass C, Lipka DB*, Heidel FH*, Fischer T*. (* Co-senior author) Epo-induced erythroid maturation is dependent on Plcy1 signaling. Cell Death Differ. 2015; 22(6): 974-985

Lipka DB*, Wang Q*, Cabezas-Wallscheid N*, Klimmeck D*, Weichenhan D, Herrmann C, Lier A, Brocks D, von Paleske L, Renders S, Wünsche P, Zeisberger P, Gu L, Haas S, Essers MAG, Brors B, Eils R, Trumpp A, Milsom MD, Plass C. (* Co-first author) Identification of DNA methylation changes at cis-regulatory elements during early steps of HSC differentiation using tagmentation-based whole genome bisulfite sequencing. Cell Cycle 2014; 13(22): 3476-3487.

Cabezas-Wallscheid N*, Klimmeck D*, Hansson J*, Lipka DB*, Reyes A*, Wang Q, Weichenhan D, Lier A, von Paleske L, Renders S, Wünsche P, Zeisberger P, Brocks D, Gu L, Herrmann C, Haas S, Essers MA, Brors B, Eils R, Huber W, Milsom MD, Plass C, Krijgsveld J, Trumpp A. (* Co-first author). Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA Methylome analysis. Cell Stem Cell 2014; 15(4): 507-522.

Brocks D, Assenov Y, Minner S, Bogatyrova O, Simon R, Koop C, Oakes C, Zucknick M, Lipka DB, Weischenfeldt J, Feuerbach L, Cowper-Sal.lari R, Lupien M, Brors B, Korbel J, Schlomm T, Tanay A, Sauter G, Gerhäuser C, Plass C. Intratumor DNA Methylation Heterogeneity Reflects Clonal Evolution in Aggressive Prostate Cancer. Cell Reports 2014; 8(3):798-806.

Poetsch AR, Lipka DB, Witte T, Claus R, Nöllke P, Zucknick M, Olk-Batz C, Fluhr S, Dworzak M, De Moerloose B, Starý J, Zecca M, Hasle H, Schmugge M, van den Heuvel-Eibrink MM, Locatelli F, Niemeyer CM, Flotho C, Plass C. RASA4 undergoes DNA hypermethylation in resistant juvenile myelomonocytic leukemia. Epigenetics 2014; 9(9):1252-1260.

Sonnet M, Claus R, Becker N, Zucknick M, Petersen J, Lipka DB, Oakes CC, Andrulis M, Lier A, Milsom MD, Witte T, Gu L, Kim-Wanner SZ, Schirmacher P, Wulfert M, Gattermann N, Lübbert M, Rosenbauer F, Rehli M, Bullinger L, Weichenhan D, Plass C. Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia. Genome Medicine 2014;6(4):34.

Wagner MC, Dziadosz M, Melo JV, Heidel F, Fischer T, Lipka DB. Nilotinib shows prolonged intracellular accumulation upon pulse-exposure: a novel mechanism for induction of apoptosis in CML cells. Leukemia 2013 Jul;27(7):1567-70. doi: 10.1038/leu.2012.364. Epub 2012 Dec 12

 

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