Control of Cellular Differentiation Trajectories for Cancer Reversion

Area of Science:

• Molecular Biology
• Computational Biology
• Genetics

Background:

• Cellular differentiation involves complex gene regulation by transcriptional regulators.
• Identifying master regulators of differentiation trajectories remains a significant challenge.

Purpose of the Study:

• To develop a computational framework for inferring master regulators of cellular differentiation.
• To identify master regulators in human large intestinal cells and assess their role in colorectal cancer.

Main Methods:

• Development of the single-cell Boolean network inference and control (BENEIN) computational framework.
• Application of BENEIN to human large intestinal single-cell transcriptome data.
• In vitro and in vivo validation of identified master regulators' effects on colorectal cancer cells.

Main Results:

• MYB, HDAC2, and FOXA2 were identified as master regulators of enterocyte differentiation.
• Inhibition of these regulators induces enterocyte differentiation.
• Simultaneous knockdown of MYB, HDAC2, and FOXA2 reverted colorectal cancer cells to a normal-like enterocyte phenotype, suppressing malignancy.

Conclusions:

• The BENEIN framework effectively identifies master regulators of cellular differentiation.
• Targeting MYB, HDAC2, and FOXA2 presents a promising strategy for colorectal cancer therapy by inducing differentiation and reducing malignancy.