Core transcriptional circuitry in human cells and methods of use thereof
Disclosed are methods for identifying the core regulatory circuitry or cell identity program of a cell or tissue, and related methods of diagnoses, screening, and treatment involving the core regulatory circuitry and/or cell identity programs identified using the methods.
1. A method comprising:
a) identifying a super-enhancer in a cancer cell or a cancer tissue using ChIP-SEQ data and identifying a group of transcription factor encoding genes whose expression is driven by the super-enhancer;
b) identifying a set of autoregulated transcription factor encoding genes from the group of transcription factor encoding genes provided in a), wherein the autoregulated transcription factor encoding genes are able to bind to the super-enhancer driving expression of the transcription factor encoding gene;
c) identifying a core regulatory circuitry of the cancer cell or tissue, wherein the core regulatory circuitry of the cancer cell or cancer tissue comprises a group of the set of autoregulated transcription factor encoding genes identified in b) which encode transcription factors that are predicted to bind to all other super-enhancers associated with driving expression of each of the other autoregulated transcription factor encoding genes of the group;
d) identifying at least one component of the core regulatory circuitry of the cancer cell or cancer tissue identified in c), and quantifying expression or activity of the at least one component with a suitable assay, wherein the at least one component of the core regulatory circuitry of the cancer cell or cancer tissue is selected from the group consisting of: a transcription factor, a transcriptional activator, a transcriptional repressor, a transcriptional co-repressor a reprogramming factor, and a cell identity gene;
e) contacting the cancer cell or cancer tissue with a test agent; and
f) measuring whether the test agent modulates the expression or activity of the at least one component of the core regulatory circuitry of the cancer cell or cancer tissue with a suitable assay, wherein a test agent that modulates the expression or activity of the at least one component of the core regulatory circuitry of the cancer cell or cancer tissue is identified as a candidate anti-cancer agent;
wherein each autoregulated transcription factor encoded by the group of autoregulated transcription factor encoding genes identified in c) is capable of binding to all other super-enhancers driving expression of each of the other autoregulated transcription factor encoding genes of the group if the super-enhancers driving expression of each of the other autoregulated transcription factor encoding genes are associated with at least one transcription factor binding motif for each of the autoregulated transcription factors of the group that is located between 10000 bp upstream and 10000 bp downstream of the super-enhancer associated with the autoregulated transcription factor encoding gene, and
wherein steps a) through c) are performed using a computer.
2. The method of claim 1 , wherein the at least one component of the core regulatory circuitry of the cancer cell or cancer tissue comprises a gene which encodes a reprogramming factor or a cell identity gene.
3. The method of claim 1 , wherein the cell comprises a cancerous blood cell.
4. The method of claim 1 , wherein the expression of the at least one component of the core regulatory circuitry of the cancer cell or cancer tissue is quantified in step d) by a hybridization based assay, a polymerase chain reaction assay, sequencing, or in situ hybridization.