Mapping the transcriptional regulatory circuits of human hematopoiesis

描述（由申请人提供）：白血病是所有人种和种族中最常见的10种癌症之一，其特征在于致癌转录因子的异常活性，导致造血分化受损。控制造血谱系的转录调控网络的系统表征将使我们能够理解致病变化的作用，改善诊断，并发现新的治疗靶点。我们实验室最近对人类造血的研究表明，数百种转录因子参与了造血的协调，其中包括在白血病易位中发现的30种转录因子。然而，由于目前的检测方法（如染色质免疫沉淀法，ChIP）的局限性，破译这些转录因子和它们的目标之间的直接连接仍然是一个难以捉摸的目标。在这里，我将建立一个全面的物理调节网络的100个谱系特异性和恶性相关的转录因子在四个主要的终末分化的人类造血细胞群体，通过采用一种新的，高通量的ChIP-seq检测由我们的实验室开发。我将使用计算算法来构建一个预测功能调控模型，该模型将物理结合网络与其控制的基因表达谱相结合。与从患者样本中测量的基因表达谱一起，该模型将用于预测恶性转录调控回路。最后，我将验证和完善该模型使用的表达谱敲除选定的关键转录因子。本研究将大大提高我们对造血分化和白血病发病机制的认识，为个性化诊断和治疗提供依据。

DESCRIPTION (provided by applicant): Leukemia, one of the top 10 most frequently occurring cancers in all races and ethnicities, is characterized by the aberrant activity of oncogenic transcription factors that lead to impaired hematopoietic differentiation. Systematic characterization of the transcriptional regulatory network controlling the hematopoietic lineage will enable us to understand the role of pathogenic changes, improve diagnosis, and discover new therapeutic targets. Very recent studies in human hematopoiesis from our laboratory show that hundreds of transcription factors participate in orchestrating hematopoiesis, including 30 that were found in translocations in leukemia. However, due to the limitations of current assays (e.g. chromatin immunoprecipitation assay, ChIP), deciphering the direct connections between these transcription factors and their targets remains an elusive goal. Here, I will build a comprehensive physical regulatory network of 100 lineage specific and malignancy-related transcription factors in the four main terminally differentiated human hematopoietic cell populations, by employing a novel, high throughput ChIP-seq assay developed by our laboratory. I will use computational algorithms to construct a predictive functional regulatory model that integrates the physical binding network with the gene expression profiles it controls. Together with gene expression profiles measured from patient's samples, the model will be used to predict malignant transcriptional regulatory circuits. Finally, I will validate and refine he model using expression profiles from knockdowns of selected key transcription factors. This study will substantially enhance our understanding of hematopoietic differentiation and leukemia pathogenesis, towards personalized diagnoses and therapeutics.