ZMBH Open PhD positions

Open PhD positions

Position no 1: Active chromatin structures at centromeres regulate chromosome segregation and mitosis

Project leader: Sylvia Erhardt

( http://www.zmbh.uni-heidelberg.de/erhardt/)

Summary:

Mitosis relies on specialized centromeric chromatin to attach condensed chromosomes to the microtubule spindle for accurate chromosome segregation. Centromeres are epigenetically distinct from their surrounding pericentric heterochromatin by the presence of the histone H3-variant Cenp-A, specific histone modifications, and kinetochore proteins during mitosis [1] . Active transcription during mitosis distinguishes centromeres from other chromatin regions. We have previouslyshown that mitotic RNA polymerase II (RNAPII) transcription and transcripts have been shown to be crucial for centromere function [2,3] ; however, the mechanisms and regulation of mitotic transcription remain poorly understood. The Erhardt lab has unpublished evidence that other active processes, for instance RNA polymerase III transcription and RNA processing and modification are required for accurate chromosome segregation (Hartmann et al. submitted). The research in the Erhardt lab is studying how transcriptional activity during mitosis is regulated and how this regulates essential centromeric structures and functions. The open project is embedded within the larger interests of the lab in transcriptional regulation at centromeric chromatin, and how centromeric chromatin is maintained during physiological and cellular stress conditions [4,5] .

References:

  1. Pauleau, A, Erhardt S. Centromere regulation: new players, new rules, new questions. Eur J Cell Biol. 2011 Oct;90(10):805-10 Review
  2. Rošić S, Köhler F, Erhardt S. Repetitive centromeric satellite RNA is essential for kinetochore formation and cell division. J. Cell Biol. 2014 Nov 10;207(3):335-49.
  3. Rošić S, Köhler F, Erhardt S. No longer a nuisance: long non-coding RNAs join CENP-A in epigenetic centromere regulation. Cell Mol Life Sci. 2016 Apr;73(7):1387-98. doi: 10.1007/s00018-015-2124-7. Review.
  4. Mathew V, Pauleau AL, Steffen N, Bergner A, Becker PB, Erhardt S. The histone-fold protein CHRAC14 influenced chromatin composition in response to DNA damage. Cell Rep. 2014 Apr 24;7(2):321-30.
  5. Bade D, Pauleau AL, Wendler A, Erhardt S. The E3 ligase CUL3/RDX controls centromere maintenance by ubiquitylating and stabilizing CENP-A in a CAL1-dependent manner. Dev Cell. 2014 Mar 10;28(5):508-19

Methods that will be used:

Drosophila genetics, cell culture, live cell, deconvolution and super resolution microscopy, ChIPseq, RNAseq, CRISPR-mediated genome engineering, protein and RNA detection methods.

Personal qualifications:

We are looking for a highly motivated and interactive PhD student with a strong background in cellular and molecular biology and a strong interest in epigenetics and chromatin biology.

Keywords:

Centromere, chromatin, transcription, epigenetic, cell cycle, RNA (coding and non-coding), mitosis.

Position no 2: Unravelling the conformation of the centromeric histone loading complex

Project Leader: Matthias Mayer and Sylvia Erhardt

Histone variants are essential for many important cellular processes, for instance in DNA damage repair by phosphorylating H2A.X at sites of DNA breaks, or for chromosome segregation by incorporating the histone variant CENP-A to centromeric chromatin regions. The precise regulation and incorporation of many histone variants into chromatin is, however, still not fully understood. This projects will focus on the essential centromere-specific histone H3 variant CENP-A and its highly regulated loading process to centromeric regions during mitosis. Specifically, we would like to understand how post-translational modifications and nucleic acids stabilize the complex and introduce conformational changes to enabling a loading-competent complex to form. We will use a wide range of techniques, including fluorescence microscopy and spectroscopy, amide hydrogen (1H/2H)-exchange in combination with high-resolution mass spectrometry.

References:

Bade D, Paulau AL, Wendler A, Erhardt S.The E3 Ligase CUL3/RDX Controls Centromere Maintenance by Ubiquitylating and Stabilizing CENP-A in a CAL1-Dependent Manner. Developmental Cell 2014 Mar 10;28(5):508-19

Rošić S, Köhler F, Erhardt S. Repetitive centromeric satellite RNA is essential for kinetochore formation and cell division. J. Cell Biol. 2014 Nov 10;207(3):335-49.

This is a collaborative project of the Mayer and Erhardt group within the ZMBH

Profile of candidate’s qualification:

We are looking for a highly motivated and interactive PhD student with a strong background in protein biochemistry and molecular biology. The ideal candidate has a strong interest in chromatin biology and enjoys being part of an international and collaborative team.

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