Bioinformatics and Cancer Genomics Laboratory

Prof Wei Shi and Prof Axel Kallies (Peter Doherty Institute)

Reconstructing Gene Regulatory Networks of Lymphopoiesis Using Multi-Omics Data Integration

The adaptive immune response is coordinated by a complex network of two cell lineages, T and B lymphocytes, generated from hematopoietic stem cells through multiple progenitor stages. Lymphopoiesis is the process of lymphocytes differentiation, which is controlled by harmonised transcription of thousands of genes through a complex Gene Regulatory Network (GRN), developing a high degree of phenotypic and functional plasticity in immune cells. Although many genes have been discovered to play a role in an adaptive immune response, the GRN underpinning this important process is poorly understood. In particular, it is unclear how the GRN regulating immune responses is disrupted in cancers such as breast cancer.

Over the last decade, advancements in genomics technologies and generating large amounts of omics data have shown a great promise in dissecting the complexity of lymphopoiesis. In parallel, there has been a growth of online databases, computational methodologies, and tools to explore multimodal data sets and integrate these multi-omics data acquisition to infer the underlying GRN. This study will utilise both public and in-house omics data, including RNA sequencing data, transcription factor chromatin immunoprecipitation followed by sequencing (ChIP-seq) data and assay for transposase-accessible chromatin with sequencing (ATAC-seq) data, to construct GRNs to unveil the molecular mechanisms underlying differentiation of B and T cells.

To construct GRNs, we will start by searching gene that co-express with major transcription factors involved in lymphopoiesis regulation. The interaction between these transcription factors and their co-expressed genes will be validated by ChIP-seq data. The association between transcription factors and chromatin accessibility will be tested by ATAC-seq data. The constructed GRNs will expand our understanding of underlying signalling and transcriptional regulation in lymphopoiesis.

We will then investigate how the expression profile of GRN is altered in breast cancer and understand the differences in expression profile changes in primary and metastatic breast cancer. We will also explore the possibility of using GRN as a tool to predict the prognosis of breast cancer patients.