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An Investigation of Noncoding Loci Involved in Lymphocyte Biology
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| 자료유형 | 학위논문 |
|---|---|
| 서명/저자사항 | An Investigation of Noncoding Loci Involved in Lymphocyte Biology. |
| 개인저자 | Harman, Christian Charles Dutton. |
| 단체저자명 | Yale University. Genetics. |
| 발행사항 | [S.l.]: Yale University., 2019. |
| 발행사항 | Ann Arbor: ProQuest Dissertations & Theses, 2019. |
| 형태사항 | 163 p. |
| 기본자료 저록 | Dissertations Abstracts International 81-03B. Dissertation Abstract International |
| ISBN | 9781085777322 |
| 학위논문주기 | Thesis (Ph.D.)--Yale University, 2019. |
| 일반주기 |
Source: Dissertations Abstracts International, Volume: 81-03, Section: B.
Advisor: Flavell, Richard A. |
| 이용제한사항 | This item must not be sold to any third party vendors. |
| 요약 | Haematopoiesis is a complex process in which fate decisions made by haematopoietic precursors help determine the eventual makeup of the blood. A subset of this process, lymphopoiesis, is responsible for development of the adaptive immune system, without which animals exhibit a greater risk of death from infection and cancer. Lymphopoiesis leads to the development and differentiation of specialized blood cells such as B and T lymphocytes that are critical in maintaining homeostasis and host immunity. The differentiation of these cells relies on a series of developmental checkpoints and selective processes that result in the repression and activation of a variety of distinct gene expression pathways. We hypothesized that noncoding loci, from which noncoding RNAs (ncRNAs) and novel small peptides are often dynamically expressed with a half-life shorter than conventional proteins, might be important in the regulation of lymphocyte biology. We performed a transcriptomic analysis in naive and effector CD4 T lymphocytes to look for noncoding transcripts that might mark such loci. We discovered a variety of dynamically expressed ncRNAs marking loci whose deletion in an in-vivo CRISPR screen affected various processes in immune cell development and function. One such locus, proximal to the transcription factor Ikaros, appears to exert control over the earliest fate decision in lymphoid lineage commitment. Deletion of this locus led to a reduction in lymphoid progenitor populations in the bone marrow and thymus in a cell-intrinsic fashion. Strikingly, in the absence of this locus, total Ikaros transcript levels remain constant, but Ikaros protein level decreases. Mice lacking this locus exhibit decreased lymphoid potential in their progenitors, and a concomitant increase in erythroid potential which we attribute to this lymphoid blockage. We believe that our results identify a novel locus that controls an early lymphoid/erythromyeloid fate decision in haematopoiesis through a novel repression of Ikaros, with important consequences on the progenitor distribution in these mice. |
| 일반주제명 | Immunology. Genetics. Developmental biology. |
| 언어 | 영어 |
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