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Elucidating biological function of genomic DNA with robust signals of biochemical activity: Integrative genome-wide studies of enhancers

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  1. Tez No: 401695
  2. Yazar: NERGİZ DOĞAN
  3. Danışmanlar: PROF. ROSS C. HARDISON
  4. Tez Türü: Doktora
  5. Konular: Mikrobiyoloji, Biyokimya, Microbiology, Biochemistry
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2014
  8. Dil: İngilizce
  9. Üniversite: The Pennsylvanıa State Unıversıty
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Biyokimya ve Moleküler Biyoloji Ana Bilim Dalı
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: Belirtilmemiş.

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Özet (Çeviri)

Genome-wide measurements of epigenetic features such as histone modifications, occupancy by transcription factors and coactivators provide the opportunity to understand more globally how genes are regulated. While much effort is being put into integrating the marks from various combinations of features, the contribution of each feature to accuracy of enhancer prediction is not known. We began with predictions of 4,915 candidate erythroid enhancers based on genomic occupancy by TAL1, a key hematopoietic transcription factor that is strongly associated with gene induction in erythroid cells. Seventy of these DNA segments occupied by TAL1 (TAL1 OSs) were tested by transient transfections of cultured hematopoietic cells, and 56% of these were active as enhancers. Sixty-six TAL1 OSs were evaluated in transgenic mouse embryos, and 65% of these were active enhancers in various tissues. Inclusion of additional epigenetic features improved the prediction accuracy, with combinations of TAL1, GATA1, EP300, H3K4me1, and H3K27ac giving high accuracy of enhancer prediction (70%-75% success depending on method of clustering) while having strong discriminatory power maintaining good sensitivity (Sn, up to 84%) and specificity (Sp, up to 80%). Importantly, it was shown that activating histone marks in the absence of key transcription factors or open chromatin profile is a weak predictor of enhancer activity, and had no discriminatory power to predict enhancers. Motifs that distinguish active from inactive TAL1 OSs implicate IRFs, STATs, and FOX protein families as candidate positive co-factors with TAL1, while REST (NRSF) and HOX family proteins are implicated in inactivity. While signals for evolutionary constraint were weak over the entire TAL1-bound DNA segments regardless of activity in either assay, phylogenetic preservation of a TF-binding site motif was associated with enhancer activity. Additionally, we reported that the conservation of GATA1 occupancy is linked to pleiotropic functions, meaning they are enhancers in multiple tissues, including non-hematopoietic tissues. Furthermore, the TAL1-bound enhancers validated in enhancer assays were assigned to their target genes and they include not only erythroid but also non-erythroid genes.

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