A hiszton módosítások dinamikájának és a transzkripció szabályozásában betöltött szerepének vizsgálata ecetmuslicában = Investigation into the dynamics and functional role of histone modifications during transcription in Drosophila melanogaster

Munkánkban két ekdizon indukálta gén, az Eip74EF és Eip75B ekdizon függő transzkripcióját befolyásoló epigenetikai mintázatokat vizsgáltuk. Jellemeztük e gének több promóterének aktivitását a harmadik lárvastádium során. Számos hiszton módosítást azonosítottunk a két gén különböző funkcionális régióiban, melyek közül öt módosítás dinamikáját, az azt létrehozó faktorokat, funkcionális hatásukat részletesen is jellemeztük. A H3K9 acetilációja ezeken a géneken jellemzően konstans, ennek ellenére ez a módosítás, melyről kimutattuk, hogy a SAGA komplex hozza létre, szükséges a két gén teljes indukciójához. További SAGA szabályozta gének vizsgálatával azt állapítottuk meg, hogy ez a módosítás a gének hozzáférhetőségét fokozhatja mind serkentő mind gátló faktorok számára. A H3K23 acetilációja a gének aktivációja során mutatható ki a két gén promóterein, így valószínűleg kritikus szerepet játszik azok szabályozásában. Kimutattuk, hogy ezt a módosítást a nejire/dCBP acetiltranszferáz hozza létre, melynek hiányában mindkét vizsgált gén transzkripciója csökkent mértékű. A H4K8, H4K12 és H4K16 acetilációja magasabb szintről közvetlenül a bábozódás előtti állapotban lecsökken. Kimutattuk, hogy a H4K8 acetilációját a gcn5 acetiltranszferáz végzi. A H4K12 acetilációjáért az ATAC komplex felelős. Erről kimutattuk, hogy részt vesz az ekdizon bioszintéziséért felelős gének szabályozásában, így e komplex kétféle mechanizmuson keresztül is kifejti hatását az ekdizon indukálta génekre. | In this study we examined the epigenetic mechanisms that influence the ecdysone dependent transcription of the Eip74EF and Eip75B ecdysone response genes. We characterized the activity of several of their promoters during the third larval instar and identified several covalent histone modifications on different functional regions of these genes. Five of these modifications were characterized in detail. Acetylation of H3K9 is constantly present on these genes. However, this modification, which we showed to be generated by the SAGA complex, is required for the complete activation of the two genes. By analyzing several other SAGA regulated genes we found that this modification increases the accessibility of genes for both stimulatory and inhibitory factors. H3K23 acetylation is characteristically established on the promoter regions of these genes during activation, thus might play a critical role in their regulation. We showed that this modification is catalyzed by the nejire/dCBP acetyltransferase, which is required for the full activation of both genes. The level of H4K8, H4K12 and H4K16 acetylation is decreased prior pupariation. We showed that acetylation of H4K8 is catalyzed by the gcn5 acetyltransferase. H4K12 is catalyzed by the SAGA complex. We showed that this complex participates in the regulation of genes of the ecdysone biosynthetic pathway, thus, this complex regulates the expression of ecdysone induced genes in two different ways

Epigenetic Regulation in Neurodegeneration Disease

Due to their often age-dependent nature, neurodegenerative diseases impact an increasing portion of modern societies [...

The Role of miR-137 in Neurodegenerative Disorders

Neurodegenerative diseases affect an increasing part of the population of modern societies, burdening healthcare systems and causing immense suffering at the personal level. The pathogenesis of several of these disorders involves dysregulation of gene expression, which depends on several molecular processes ranging from transcription to protein stability. microRNAs (miRNAs) are short non-coding RNA molecules that modulate gene expression by suppressing the translation of partially complementary mRNAs. miR-137 is a conserved, neuronally enriched miRNA that is implicated in neurodegeneration. Here, we review the current body of knowledge about the role that miR-137 plays in five prominent neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. The presented data indicate that, rather than having a general neuroprotective role, miR-137 modulates the pathology of distinct disorders differently

DNA Methylation in Huntington’s Disease

Methylation of cytosine in CpG dinucleotides is the major DNA modification in mammalian cells that is a key component of stable epigenetic marks. This modification, which on the one hand is reversible, while on the other hand, can be maintained through successive rounds of replication plays roles in gene regulation, genome maintenance, transgenerational epigenetic inheritance, and imprinting. Disturbed DNA methylation contributes to a wide array of human diseases from single-gene disorders to sporadic metabolic diseases or cancer. DNA methylation was also shown to affect several neurodegenerative disorders, including Huntington’s disease (HD), a fatal, monogenic inherited disease. HD is caused by a polyglutamine repeat expansion in the Huntingtin protein that brings about a multifaceted pathogenesis affecting several cellular processes. Research of the last decade found complex, genome-wide DNA methylation changes in HD pathogenesis that modulate transcriptional activity and genome stability. This article reviews current evidence that sheds light on the role of DNA methylation in HD

The histone replacement gene His4r is involved in heat stress induced chromatin rearrangement

His4r is the only known variant of histone H4 in Drosophila. It is encoded by the His4r single-copy gene that is located outside of the histone gene cluster and expressed in a different pattern than H4, although the encoded polypeptides are identical. We generated a null mutant (His4rΔ42) which is homozygous viable and fertile without any apparent morphological defects. Heterozygous His4rΔ42 is a mild suppressor of position-effect variegation, suggesting that His4r has a role in the formation or maintenance of condensed chromatin. Under standard conditions loss of His4r has a modest effect on gene expression. Upon heat-stress the induction of the Heat shock protein (HSP) genes Hsp27 and Hsp68 is stronger in His4rΔ42 mutants with concordantly increased survival rate. Analysis of chromatin accessibility after heat shock at a Hsp27 regulatory region showed less condensed chromatin in the absence of His4r while there was no difference at the gene body. Interestingly, preconditioning before heat shock led to increased chromatin accessibility, HSP gene transcription and survival rate in control flies while it did not cause notable changes in His4rΔ42. Thus, our results suggest that His4r might play a role in fine tuning chromatin structure at inducible gene promoters upon environmental stress conditions

Functional characterization and gene expression profiling of Drosophila melanogaster short dADA2b isoform-containing dSAGA complexes

The data presented here are in accord with results of genetic complementation experiments, and support the hypothesis that different isoforms of dADA2b contribute to the functional variations of dSAGA multiprotein HAT complexes