Lymphoid to Myeloid Cell Trans-Differentiation Is Determined by C/EBPβ Structure and Post-Translational Modifications

Abstract

The transcription factor C/EBPβ controls differentiation, proliferation, and functionality of many cell types, including innate immune cells. A detailed molecular understanding of how C/EBPβ directs alternative cell fates remains largely elusive. A multitude of signal-dependent post-translational modifications (PTMs) differentially affect the protean C/EBPβ functions. In this study we apply an assay that converts primary mouse B lymphoid progenitors into myeloid cells in order to answer the question how C/EBPβ regulates (trans-) differentiation and determines myeloid cell fate. We found that structural alterations and various C/EBPβ PTMs determine the outcome of trans-differentiation of lymphoid into myeloid cells, including different types of monocytes/macrophages, dendritic cells, and granulocytes. The ability of C/EBPβ to recruit chromatin remodeling complexes is required for the granulocytic trans-differentiation outcome. These novel findings reveal that PTMs and structural plasticity of C/EBPβ are adaptable modular properties that integrate and rewire epigenetic functions to direct differentiation to diverse innate immune system cells, which are crucial for the organism survival.

A Negative Feedback Loop of Transcription Factors Specifies Alternative Dendritic Cell Chromatin States

“…Similarly, Irf8 knockdown or Cebpb over-expression shifted pDC towards a “moDC state”. These results are consistent with experiments showing that Cebpb overexpression trans-differentiates lymphocytes into myelocytes (Stoilova et al, 2013; Xie et al, 2004). …”

Non‐steady‐state hematopoiesis regulated by the C/EBPβ transcription factor

“…Both LAP* and LAP are transcriptional activators, whereas LIP (which is the shortest isoform and lacks transactivation domains but retains DNA binding and dimerization domains) acts as a repressor or a dominant negative inhibitor of other C/EBP family transcription factors . The ratio of these isoforms is regulated by different signaling events and has a significant impact on the overall function of C/EBPβ …”

Erdheim-Chester Disease and Small Lymphocytic Lymphoma Collision Tumour Presenting as a Perirenal Mass

“…The cases of CLL occurring with haemophagocytic lymphohistiocytosis have also been described [27]. Epigenetic mechanisms as well as transcription factors involved in lineage determination have been implicated in this divergent differentiation model of a collision tumour [28]. Another well-studied example is transformation of follicular lymphoma into diffuse large B cell lymphoma.…”