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Systematic Genetic Dissection of Human Erythropoiesis

人类红细胞生成的系统遗传解剖

基本信息

批准号：
10629304
负责人：
Vijay Ganesh Sankaran
金额：
$ 39.83万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-20 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10629304
关键词：
Address Affect Anemia Biological Biological Assay Biology CRISPR interference CRISPR/Cas technology Cell Line Cells Complex Data Disease Dissection Emerging Technologies Enhancers Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis Funding Gene Expression Genes Genetic Genetic Polymorphism Genetic Variation Genetic study Genomics Genotype Goals Grant Health Hematopoietic Human Human Genetics Impairment Individual Laboratories Link Maps Morbidity - disease rate National Institute of Diabetes and Digestive and Kidney Diseases Pattern Population Process Production Pronormoblasts Regulator Genes Regulatory Element Reporter Resolution Shapes Source Techniques Therapeutic Untranslated RNA Variant Work causal variant follow-up functional genomics gene interaction genome editing genome wide association study genome-wide analysis genomic data genomic tools human disease innovation insight mortality novel novel strategies novel therapeutic intervention progenitor promoter success technology development tool trait

项目摘要

Project Summary/ Abstract Humans vary considerably in the process of red blood cell production (erythropoiesis). Such variation contributes to diseases, including numerous forms of anemia. Much of this variation is attributable to genetic polymorphisms found in the population. However, as with most other complex diseases and traits, how such variation impacts the process of erythropoiesis remains poorly understood. We have made tremendous progress in beginning to decipher how human genetic variation impacts erythropoiesis during the first five years of this grant from the NIDDK. We have pioneered the use of massively parallel reporter assays as an approach to systematically dissect how non-coding genetic variation revealed from genome-wide association studies (GWAS) functionally impacts transcriptional regulatory elements. We have also utilized CRISPR/Cas9 genome editing to bolster these findings in an endogenous context. In this competitive renewal application, we aim to invigorate these studies and directly address how human genetic variation shapes the non-coding genomic landscape of erythropoiesis. We will build upon our prior studies and use innovative new approaches to ask these questions in primary human erythroid cells. We have recently conducted one of the largest GWAS of erythroid traits and have identified over 1,800 distinct associated loci. We propose to utilize a number of cutting-edge genomic tools that will allow us to gain important insights from these emerging large-scale genetic studies. First, we aim to define putative causal variants underlying these associations and their functional effects on the linked transcriptional regulatory elements. Second, we will systematically identify target genes that may be affected by the regulatory elements harboring trait-associated variation. Finally, we will dissect mechanisms of action by which a subset of these variants impact target genes and alter human erythropoiesis. Not only will the proposed studies over the next five years significantly advance our understanding of human erythropoiesis and related diseases, but this work will also serve as a paradigm for the systematic dissection of other complex diseases and traits.

项目总结/摘要人类在红细胞生成（红细胞生成）过程中差异很大。这种变化导致疾病，包括多种形式的贫血。这种变异大部分可归因于遗传在人群中发现的多态性。然而，与大多数其他复杂疾病和特征一样，变异对红细胞生成过程的影响仍然知之甚少。我们取得了巨大在开始破译人类遗传变异如何影响前五年的红细胞生成方面取得了进展这是NIDDK多年来的资助。我们率先使用大规模并行报告基因测定作为一种系统地剖析非编码遗传变异如何从全基因组关联中揭示的方法 GWAS研究（GWAS）在功能上影响转录调控元件。我们还利用了CRISPR/Cas9 基因组编辑以支持内源性背景下的这些发现。在这次竞争性的续约申请中，我们旨在振兴这些研究，并直接解决人类遗传变异如何塑造非编码基因，红细胞生成的基因组景观。我们将在先前研究的基础上，采用创新的新方法在原代人类红细胞中提出这些问题。我们最近进行了一次最大的GWAS 红细胞性状的研究，并确定了超过1,800个不同的相关基因座。我们建议利用一些尖端的基因组工具，使我们能够从这些新兴的大规模遗传学中获得重要的见解，问题研究首先，我们的目标是定义这些关联背后的假定因果变量及其功能对连接的转录调控元件的影响。其次，我们将系统地鉴定靶基因这可能会受到携带性状相关变异的调节元件的影响。最后，我们将解剖这些变体的子集通过其影响靶基因并改变人红细胞生成的作用机制。未来五年的研究不仅将大大促进我们对人类的理解，红细胞生成和相关疾病，但这项工作也将作为一个范例，系统解剖其他复杂的疾病和特征。

项目成果

期刊论文数量（53）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Scalable, multimodal profiling of chromatin accessibility, gene expression and protein levels in single cells.

DOI：
10.1038/s41587-021-00927-2
发表时间：
2021-10
期刊：
Nature biotechnology
影响因子：
46.9
作者：
Mimitou EP;Lareau CA;Chen KY;Zorzetto-Fernandes AL;Hao Y;Takeshima Y;Luo W;Huang TS;Yeung BZ;Papalexi E;Thakore PI;Kibayashi T;Wing JB;Hata M;Satija R;Nazor KL;Sakaguchi S;Ludwig LS;Sankaran VG;Regev A;Smibert P
通讯作者：
Smibert P

Deciphering cell states and genealogies of human haematopoiesis.

破译细胞状态和人类造血的谱系。

DOI：
10.1038/s41586-024-07066-z
发表时间：
2024
期刊：
Nature
影响因子：
64.8
作者：
Weng,Chen;Yu,Fulong;Yang,Dian;Poeschla,Michael;Liggett,LAlexander;Jones,MatthewG;Qiu,Xiaojie;Wahlster,Lara;Caulier,Alexis;Hussmann,JeffreyA;Schnell,Alexandra;Yost,KathrynE;Koblan,LukeW;Martin-Rufino,JorgeD;Min,Joseph;Ha
通讯作者：
Ha

Purifying Selection against Pathogenic Mitochondrial DNA in Human T Cells.

DOI：
10.1056/nejmoa2001265
发表时间：
2020-10-15
期刊：
The New England journal of medicine
影响因子：
0
作者：
Walker MA;Lareau CA;Ludwig LS;Karaa A;Sankaran VG;Regev A;Mootha VK
通讯作者：
Mootha VK

Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic EPO Mutation.

DOI：
10.1016/j.cell.2017.02.026
发表时间：
2017-03-09
期刊：
Cell
影响因子：
64.5
作者：
Kim AR;Ulirsch JC;Wilmes S;Unal E;Moraga I;Karakukcu M;Yuan D;Kazerounian S;Abdulhay NJ;King DS;Gupta N;Gabriel SB;Lander ES;Patiroglu T;Ozcan A;Ozdemir MA;Garcia KC;Piehler J;Gazda HT;Klein DE;Sankaran VG
通讯作者：
Sankaran VG

I SPI1 something needed for B cells.