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Genome-wide regulation of Suv39h-dependent mouse heterochromatin

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  1. Tez No: 402931
  2. Yazar: AYDAN KARSLIOĞLU
  3. Danışmanlar: PROF. DR. THOMAS JENUWEIN
  4. Tez Türü: Doktora
  5. Konular: Biyoloji, Biology
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2012
  8. Dil: İngilizce
  9. Üniversite: Albert-Ludwigs-Universität Freiburg im Breisgau
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Biyoloji Ana Bilim Dalı
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: 130

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Özet (Çeviri)

This PhD thesis focuses on the underlying principles of heterochromatin formation. Two projects were followed to elucidate mechanisms which contribute to heterochromatin formation. In the first project, we studied the regulation of mouse pericentric heterochromatin. Its repetitive nature and generation of heterochromatic transcripts are among determinants of chromatin compaction at pericentric heterochromatin. Following these leads, we investigated the possibility of transcription factor-based regulation at pericentric heterochromatin. Here we provide evidence for regulation of major satellite transcription by redundant activity of sequence-specific transcription factors Pax3 and Pax9. Depletion of these repressive factors lead to upregulation of heterochromatic transcripts, dispersion of repressive marks and aberrant chromosome segregation. Bioinformatic analysis of transcription factor binding motives at heterochromatin vs. euchromatin resolved distinct arrangements, such as reiterated and stochastic distribution at heterochromatin vs. defined and concentrated distribution at euchromatin. These findings revealed an intrinsic difference between the two types of chromatin at the DNA level, thereby contributing novel insights. This work was published as first-author publication (Bulut-Karslioglu, A., Perrera, V., Scaranaro, M., de la Rosa-Velazquez, I.A., van de Nobelen, S., Shukeir, N., Popow, J., Gerle, B., Opravil, S., Pagani, M., et al., A transcription factor-based mechanism for mouse heterochromatin formation, Nat Struct Mol Biol., 2012 Sep 16) In the second project, we aimed to determine targets of Suv39h histone methyltransferases outside pericentric heterochromatin. Suv39h enzymes are upstream regulators in formation of pericentric heterochromatin, yet little is known about Suv39h function outside this compartment. We generated Suv39h-HA/Flag knock-in embryonic stem cells and profiled genome-wide Suv39h binding sites by ChIP-sequencing. Our findings demonstrate Suv39h involvement in selective repression of mobile genomic elements, namely intact LINE and LTR retrotransposons. Loss of Suv39h function induces transcriptional activity of these interspersed repeats. In contrast to pericentric heterochromatin, Suv39h-dependent retrotransposon silencing is not constitutive, but appears to be unique to embryonic stem cells. In addition to repressing retrotransposons, Suv39h-dependent heterochromatin indirectly influences euchromatic gene regulation, since altered gene expression was observed in Suv39h1/Suv39h2 double null ESCs. Findings from this project were integrated into a manuscript and presented as such in this thesis. Further results are explained separately in Chapter 3. In summary, results and insights presented in this study contribute to our understanding of regulatory processes, which govern Suv39h-dependent heterochromatin formation.

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