H2020Индивидуална стипендия2016–2018

XPGCS · Single cell profiling of X chromosome reactivation during primordial germ cell specification in vivo

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2016-03-01 → 2018-04-17
Финансиране от ЕС: 195 455 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Предмет на анализа е как се активира „изключеният“ Х-хромозома в женските зародишни клетки, например чрез премахване на специфични протеини от ДНК. Процесът помага за разбирането на епигенетичното наследство и развитието на регенеративната медицина.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Single cell profiling of X chromosome reactivation during primordial germ cell specification in vivo

"Mammalian primordial germ cells (PGCs) are the precursors of eggs and sperm and transmit genetic and epigenetic information to subsequent generations. Following fertilization, these highly specialised gametic cells combine to form a totipotent zygote, which will develop into a new organism. Epigenetic reprogramming in early PGCs is critical towards generating the totipotent state, which includes reactivation of the inactive X chromosome (Xi) in female germ cells. However, the molecular events associated with XCR remain to be fully elucidated. Indeed, XCR is also a key hallmark of female somatic cell reprogramming to a totipotent/pluripotent state, so this investigation has broader implications for regenerative medicine and epigenetic inheritance in development and disease. In mammals, one of the two Xs is transcriptionally silenced in females for dosage compensation between gender and enriched in ""repressive"" chromatin marks such as H3K27 methylation. In the mouse, XCR occurs at two different time point: in the inner cell mass of the blastocyst and during the PGC differentiation. During reactivation, the Xi undergoes reprogramming through the loss of Xist RNA coating, followed by the erasure of the repressive H3K27me3 histone mark, and biallelic expression of X-linked genes. Despite this knowledge, little is known about the gene-activation dynamics, or the mechanisms involved both in the ICM and the PGC. The overall aim of this project was to study the functional association between changes in X-linked gene expression and the dynamic changes in chromatin associated with reprogramming of the Xi. My specific objectives were to study the key time points of in vivo X-chromosome reprogramming as follows: - Investigation of X-linked gene activity, at the scale of the entire X chromosome, during PGC differentiation. - Mapping of H3K27me3 enriched chromatin and its correlation with gene expression along the X chromosome - The ability of H3K27me3 enriched chromatin to repress X linked gene expression, and more generally to be a switch against X chromosome reactivation."

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

In female mice, one of the two X chromosomes is inactivated during early development to ensure dosage compensation between genders. A long non-coding gene, Xist, plays a crucial role in the initiation of the X chromosome inactivation (XCI) process. Primordial germ cells (PGCs), the precursors of sperm and eggs, transmit genetic and epigenetic information to subsequent generations, following extensive reprogramming, erasure of methylation and genomic imprints, and X chromosome reactivation. The inactive X (Xi) then undergoes progressive reprogramming and reactivation in the germline of female embryos, through the loss of Xist RNA coating, followed by the erasure of the repressive H3K27me3 histone mark, and eventually biallelic expression of X-linked genes.Although the global dynamics of Xi reactivation have been mapped little is known about the gene-specific dynamics, or the mechanisms involved. To explore gene activity on the entire X chromosome during reprogramming in the germline, I will perform single-cell transcriptome analyses on PGCs from C57BL/6 X Castaneus F1 female hybrid embryos. The high rate of sequence polymorphisms between these strains provides allele-specific information for the activity of the Xp (paternal X) and the Xm (maternal X). I will investigate the kinetics of Xp and Xm gene reactivation chromosome-wide at the single cell level following PGC specification. Furthermore, I will study the dynamics of the expression of X-linked genes in conjunction with chromatin changes in PGCs by monitoring the loss of H3K27me3 enrichment on the inactive X chromosome. In parallel, I will study how the regulation of H3K27me3 affect Xi reactivation by using a conditional mutant mouse model of a H3K27me3 demethylase, UTX. Altogether, the innovative and multidisciplinary approach of this study will unravel important insights on germline reprogramming and the roles of chromatin changes associated with X chromosome reactivation.

Оригинален текст от CORDIS (на английски).

Участници

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGEКоординаторОбединеното кралство