Dissecting the epigenetic landscapes of hematopoiesis and fission yeast
Author: Rönnerblad, Michelle
Date: 2014-03-27
Location: Hörsal Månen (9Q), Alfred Nobels allé 8, Karolinska Institutet, Huddinge
Time: 10.00
Department: Inst för biovetenskaper och näringslära / Dept of Biosciences and Nutrition
Abstract
The genome of eukaryotic cells is stored in the nucleus as chromatin, a DNA-protein complex that serves to compact and protect the DNA molecules. The basic unit of chromatin is the nucleosome composed of DNA wrapped around a histone protein core. In addition to condensing and protecting the genome, chromatin confers a number of regulatory properties employed for example in control of gene expression and stabilization of repetitive sequences. Chromatin also constitutes an obstacle that needs to be negotiated in processes such as transcription elongation, DNA replication and DNA repair. A wide range of chromatin modifying factors and mechanisms are involved in regulating the state of chromatin and affect all DNA related processes. These mechanisms, often referred to as epigenetic, include methylation of DNA, regulation by non-coding RNAs, remodeling of nucleosomes, posttranslational modifications of histones and incorporation of variant histones. The resulting chromatin state is called the epigenome and can, in contrast to the underlying DNA sequence, differ between cells in the same organism.
This thesis describes characterization of aspects of the egipenomes of hematopoietic cells and fission yeast. We show that in fission yeast, genes with related functions share common patterns of histone modifications in the promoter regions. We also demonstrate crosstalk between different histone modifications, including interdependence of histone H4 acetylation sites and regulatory roles of histone methylation for histone acetylation.
To better understand how chromatin factors influence human blood development we analysed expression of genes encoding chromatin modifying proteins in the hematopoietic system, including the hematopoietic stem cells and a wide range of mature blood cells. In doing so we could identify epigenetic factors that were expressed in cell type, cell lineage or cancer specific patterns, implicating them in regulation of blood development. We also found that several genes display differential use of alternative transcription start sites between cell types.
Finally we constructed an in-depth map of how DNA methylation and gene expression changes during human granulocyte development. Our experiments show that DNA methylation changes are linked to points of lineage restriction, implicating DNA methylation in control of cell fate. DNA methylation changes, most of which were decreases, were primarily located outside of CpG islands, which have been the focus of most DNA methylation studies historically. Interestingly, DNA methylation was especially dynamic in enhancer elements, and sites with decreasing DNA methylation overlapped with differentiation induced enhancers and increased expression of target genes. This result suggests a role of DNA methylation in regulating enhancer activity in granulopoiesis.
This thesis describes characterization of aspects of the egipenomes of hematopoietic cells and fission yeast. We show that in fission yeast, genes with related functions share common patterns of histone modifications in the promoter regions. We also demonstrate crosstalk between different histone modifications, including interdependence of histone H4 acetylation sites and regulatory roles of histone methylation for histone acetylation.
To better understand how chromatin factors influence human blood development we analysed expression of genes encoding chromatin modifying proteins in the hematopoietic system, including the hematopoietic stem cells and a wide range of mature blood cells. In doing so we could identify epigenetic factors that were expressed in cell type, cell lineage or cancer specific patterns, implicating them in regulation of blood development. We also found that several genes display differential use of alternative transcription start sites between cell types.
Finally we constructed an in-depth map of how DNA methylation and gene expression changes during human granulocyte development. Our experiments show that DNA methylation changes are linked to points of lineage restriction, implicating DNA methylation in control of cell fate. DNA methylation changes, most of which were decreases, were primarily located outside of CpG islands, which have been the focus of most DNA methylation studies historically. Interestingly, DNA methylation was especially dynamic in enhancer elements, and sites with decreasing DNA methylation overlapped with differentiation induced enhancers and increased expression of target genes. This result suggests a role of DNA methylation in regulating enhancer activity in granulopoiesis.
List of papers:
I. Sinha I, Buchanan L, Rönnerblad M, Bonilla C, Durand-Dubief M, Shevchenko A, Grunstein M, Stewart AF, Ekwall K (2010). Genome-wide mapping of histone modifications and mass spectrometry reveal H4 acetylation bias and H3K36 methylation at gene promoters in fission yeast. Epigenomics. 2010 2(3):377-93.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Prasad P, Rönnerblad M, Arner E, Itoh M, Kawaji H, Lassman T, Daub C, Forrest AR, the FANTOM consortium, Andreas Lennartsson, Karl Ekwall. High-throughput transcription profiling identifies putative epigenetic regulators of hematopoiesis. [Accepted]
Pubmed
View record in Web of Science®
III. Rönnerblad M, Andersson R, Olofsson T, Douagi I, Karimi M, Lehmann S, Hoof I, de Hoon M, Itoh M, Nagao-Sato S, Kawaji H, Lassman T, Carnici P, Hayashizaki Y, Forrest AR, Sandelin A, the FANTOM consortium, Ekwall K, Arner E, Lennartsson A. Analysis of the DNA methylome and transcriptome in granulopoieis reveal timed changes and dynamic enhancer methylation. [Accepted]
Pubmed
View record in Web of Science®
I. Sinha I, Buchanan L, Rönnerblad M, Bonilla C, Durand-Dubief M, Shevchenko A, Grunstein M, Stewart AF, Ekwall K (2010). Genome-wide mapping of histone modifications and mass spectrometry reveal H4 acetylation bias and H3K36 methylation at gene promoters in fission yeast. Epigenomics. 2010 2(3):377-93.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Prasad P, Rönnerblad M, Arner E, Itoh M, Kawaji H, Lassman T, Daub C, Forrest AR, the FANTOM consortium, Andreas Lennartsson, Karl Ekwall. High-throughput transcription profiling identifies putative epigenetic regulators of hematopoiesis. [Accepted]
Pubmed
View record in Web of Science®
III. Rönnerblad M, Andersson R, Olofsson T, Douagi I, Karimi M, Lehmann S, Hoof I, de Hoon M, Itoh M, Nagao-Sato S, Kawaji H, Lassman T, Carnici P, Hayashizaki Y, Forrest AR, Sandelin A, the FANTOM consortium, Ekwall K, Arner E, Lennartsson A. Analysis of the DNA methylome and transcriptome in granulopoieis reveal timed changes and dynamic enhancer methylation. [Accepted]
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Lennartsson, Andreas
Issue date: 2014-03-05
Rights:
Publication year: 2014
ISBN: 978-91-7549-465-4
Statistics
Total Visits
Views | |
---|---|
Dissecting ...(legacy) | 1035 |
Dissecting ... | 174 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Dissecting ... | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
File Visits
Views | |
---|---|
Thesis_Michelle_Ronnerblad.pdf(legacy) | 1061 |
Spikblad_Michelle_Ronnerblad.pdf(legacy) | 506 |
Thesis_Michelle_Ronnerblad.pdf | 107 |
Spikblad_Michelle_Ronnerblad.pdf | 78 |
Top country views
Views | |
---|---|
United States | 477 |
China | 154 |
Sweden | 126 |
Germany | 83 |
Finland | 13 |
South Korea | 12 |
France | 11 |
Japan | 10 |
Denmark | 9 |
Russia | 9 |
Top cities views
Views | |
---|---|
Sunnyvale | 74 |
Ashburn | 49 |
Stockholm | 46 |
Shenzhen | 43 |
Kiez | 30 |
Beijing | 14 |
Seoul | 12 |
Berlin | 10 |
Cupertino | 9 |
Uppsala | 8 |