The unique metabolic characteristics and diverse functions of marrow adipose tissue (MAT) have drawn more attention recently. Previously, we have reported that CBFA2T2 is required for BMP2-induced osteogenic differentiation of mesenchymal stem/stromal cells (MSCs). In the present study, we further investigated the role of CBFA2T2 in regulation of adipogenic differentiation in mouse bone marrow-derived MSCs (mBMSCs) and human dental pulp stem cells (hDPSCs). We found CBFA2T2 expression was dramatically upregulated during adipogenesis of mBMSCs and hDPSCs. More importantly, knockdown of CBFA2T2 in mBMSCs and hDPSCs significantly inhibited the process of adipogenic differentiation, as revealed by the expression of adipogenic markers and Oil Red O staining. Mechanistically, we found knockdown of CBFA2T2 led to an increase in H3K9me2 and H3K9me3 levels at promoter of CEBPA, an essential transcription factor of adipogenesis. Taken together, these findings suggest CBFA2T2 is key regulator of adipogenic differentiation of MSCs, and it may represent a therapeutic target for conditions with excessive MAT. (C) 2020 Elsevier Inc. All rights reserved.