Histoonide post-translatsiooniliste modifikatsioonide uurimine RNA polümeraas II-sõltuvas transkriptsioonis

Väitekirja elektrooniline versioon ei sisalda publikatsiooneEukarüootsetes rakkudes on DNA pakitud koos histoonivalkudega struktuuri, mida nimetatakse kromatiiniks. DNA tihedalt kromatiini pakkimine tagab geneetilise materjali kompaktsuse, kui samas on see dünaamiline struktuur, mis võimaldab ligipääsu erinevatele DNA-l toimuvatele protsessidele, kaasa arvatud RNA polümeraas II-e poolt läbiviidavale geenide transkriptsioonile. Üheks peamiseks mehhanismiks kromatiini struktuuri muutmiseks rakus on histoonide modifitseerimine. Histoonide post-translatsioonilised modifikatsioonid (PTM-d) võivad muuta nii DNA ja histoonide vahelisi interaktsioone kui olla seondumiskohaks erinevatele efektorvalkudele, mis omakorda toovad transkriptsioonifaktorid ja regulatoorsed valgud teatud DNA piirkondadele. On leitud, et PTM-d on vajalikud kromatiini ja transkriptsiooni epigeneetilises reguleerimises, kuid milliste mehhanismide abil ja kuidas toimub modifikatsioonimustrite dünaamiline regulatsioon transkriptsioonis on veel selguseta. Käesolevas töös uuriti RNAPII transkriptsiooni mehhanisme ning histoonide PTM-ide ja nendele seonduvate faktorite rolli, kasutades mudelorganismina pagaripärmi Saccharomyces cerevisiae. Esmalt vaadeldi transkriptsiooni käigus moodustuva histoon H3 lüsiinijääk 36 metülatsioonimustri (H3K36) levikut ja eemaldamise dünaamikat. Leiti, et metüleerimine püsib rakkudes pärast transkriptsiooni toimumist võrdlemisi lühiajaliselt ning metülatsioonimärgise eemaldamiseks on vajalik nii demetülaaside ensümaatiline aktiivsus kui replikatsiooni käigus toimuv histoonide väljavahetamine. Järgnevalt uuriti histoonide modifikatsioonide mõju geeniekspressioonile olukorras, kus RNAPII kompleksist puudub üks subühik. Leiti, et sellistes stressitingimustes ei suuda rakud korrektselt reageerida tekkivatele DNA kahjustustele ning histoonide atsetüleerimine muutub rakkude elus püsimiseks hädavajalikuks. Antud töös uuriti ka atsüleerimist äratundva efektorvalgu Taf14 YEATS domeeni olulisust ja rolli transkriptsioonis. Täpsustati YEATS domeeni seondumissihtmärke ja leiti, et YEATS domeen osaleb transkriptsiooni pre-initsatsiooni kompleksi stabiliseerimises. Doktoritöö tulemused avardavad oluliselt teadmisi histoonide modifikatsioonide ja nendega seonduvate valkude olulisusest transkriptsiooni regulatsioonis.In eukaryotic cells, DNA is packed with histone proteins into a complex called chromatin. Although DNA is very tightly folded, chromatin structure is dynamic and becomes available to the enzymes and processes that take place on the DNA template, including RNA polymerase II-mediated (RNAPII) gene transcription. One of the key factors that control DNA accessibility are post-translational modifications (PTMs) of histones. PTMs can either directly influence chromatin compaction or serve as binding sites for effector proteins recognizing these marks and recruiting transcription machinery or regulatory factors to specific DNA regions. It is well established that PTMs are crucial in epigenetic regulation of chromatin and transcription, but several aspects of their mechanistic details and regulatory dynamics are still not known. This thesis explores the mechanisms of RNAPII transcription and PTMs and their binding factors using Saccharomyces cerevisiae as a model. To clarify how epigenetic landscapes are established and maintained, the spreading and turnover mechanisms of the methylation pattern of histone H3 lysine 36 (H3K36) was evaluated. This study demonstrates a relatively short-term persistence of methylation after recently occurred transcription and replication-dependent dilution and passive demethylation by demethylases contribute to the turnover of H3K36 methylation mark. The second objective of this study was to explore the importance of histone modifications in cells where transcription is hampered by depletion of one of the RNAPII subunits. It was found that in these stress conditions cells are not able to respond to occurring DNA damage and histone acetylation becomes essential for cell viability. In addition, this study analysed the essentiality and role of effector protein Taf14 reader domain YEATS that binds to acylated histones. The interaction targets of YEATS domain were clarified in vivo and found that it participates in transcription pre-initiation complex stabilization. Results presented in this thesis create new knowledge on the molecular mechanisms of transcriptional regulation and the involvement of PTMs and their reader proteins

Looking for the Bird in Chinese Pidgin English: Cross-Linguistic Influence in the Use of Some Key Function Words

This paper is a study of the cross-linguistic influence (CLI) evident in 19th century Chinese Pidgin English (CPE). Here, 'cross-linguistic' is mean as the crossbreeding of substrate and superstrate languages. This hybridization is essential to the particular character of pidgins and creole and, in my opinion, responsible for the production of features that are not the sole property of any single parent. We will be examining four different types of productive CPE features that can reasonably be traced to origins in one of three source languages but are not entirely explainable by recourse to any one itlone. The interaction between linguistic partners is visible in shaping the common ground on which they can productively engage. The CPE function words that are the focus of this study are the prepositionlong, the classifier ptiece, the noun compounds and suffixes, and the verbal marker make. The source languages traced are Cantonese, English, and Hindustani

Aneurismas espotâneos com localização rara: a propósito de dois casos

Os autores relatam dois casos de aneurisma arterial espontâneo com localização relativamente rara: um da pediosa, e outro de ramo da artéria isquiática. Os dois casos foram documentados por arteriografia e ambos foram operados com pleno êxito. O aneurisma da pediosa foi extirpado e o de ramo da isquiática foi tratado por endoaneurismorrafia obliterante de Matas

Writing in Britain and Ireland, c. 400 to c. 800

No abstract available

Old English macian, Its Origin and Dissemination

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66612/2/10.1177_007542428601900105.pd

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