Reprogramming of B lymphocytes into macrophages by enforced transcription factor expression

Reprogramming of B lymphocytes into macrophages by enforced transcription factor expression

We are interested in how transcription factors (TFs) instruct immature cells to acquire specific functions and shapes during differentiation into specialized cells. TFs are proteins that bind to specific DNA sequences and are required to establish and maintain cell type specific gene expression programs. To test the cell type (or lineage) instructive potential of a given TF we express it in cells where it is not normally present and determine whether these cells transdifferentiate into the TF-associated cell type.

Using this approach we found that normal B cells (including immunoglobulin expressing cells) can be reprogrammed by enforced expression of the TF C/EBPalpha, which is expressed at high levels in macrophages and granulocytes and is required for the formation and function of these cells. The reprogramming occurs within 2 to 4 days and is uniquely efficient (up to 100%), generating functional macrophages that retain immunoglobulin rearrangements. C/EBPa reprograms mouse and human B cells by silencing thousands of lymphocyte associated genes and by activating similar numbers of macrophage genes, co-operating with PU.1, a TF expressed at low levels in B cells (Xie et al., Cell, 2004: Bussmann et al., Cell Stem Cell, 2009; DiTullio et al., PNAS, 2011).

Using an inducible form of C/EBPa, with which reprogramming can be synchronously initiated, we are currently studying how the factor silences and activates genes and how it induces genome-wide chromatin changes.