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.

项目摘要/摘要人类在红细胞产生（红细胞生成）的过程中有很大差异。这种变化有助于疾病，包括多种形式的贫血。这种变化的大部分归因于遗传人口中发现的多态性。但是，与大多数其他复杂疾病和特征一样变异会影响促红细胞生成的过程仍然很少了解。我们做出了巨大的开始在前五个中开始破译人类遗传变异如何影响促红细胞生成的进展 NIDDK的这笔赠款年。我们已经开创了大量平行的记者测定法作为一个系统地剖析非编码遗传变异的方法研究（GWAS）在功能上影响转录调节元件。我们还使用了CRISPR/CAS9 基因组编辑以在内源性环境中加强这些发现。在此竞争性更新申请中，我们旨在激发这些研究并直接解决人类遗传变异如何塑造非编码促红细胞生成的基因组景观。我们将基于先前的研究并使用创新的新方法在原代人红细胞中提出这些问题。我们最近进行了最大的GWA之一红细胞性状，并确定了1,800多个不同的相关基因座。我们建议利用许多尖端的基因组工具将使我们能够从这些出现的大规模遗传中获得重要的见解研究。首先，我们旨在定义这些关联及其功能的基础的假定因果变体对链接的转录调节元件的影响。其次，我们将系统地识别目标基因这可能会受到具有与性状相关变化的调节元素的影响。最后，我们将剖析这些变体的子集会影响靶基因并改变人类红细胞生成的作用机制。未来五年内提议的研究不仅会显着提高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系统解剖的范式其他复杂疾病和特征。

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）

Patchwork Cancer Predisposition.

DOI：
10.1158/2159-8290.cd-22-0025
发表时间：
2022-04-01
期刊：
Cancer discovery
影响因子：
28.2
作者：
Liggett LA;Sankaran VG
通讯作者：
Sankaran VG

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

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

Purifying Selection against Pathogenic Mitochondrial DNA in Human T Cells.