TY - JOUR T1 - Alu-mediated weak CEBPA binding and slow B cell transdifferentiation in human JF - bioRxiv DO - 10.1101/2021.10.28.466072 SP - 2021.10.28.466072 AU - Ramil Nurtdinov AU - María Sanz AU - Amaya Abad AU - Alexandre Esteban AU - Sebastian Ullrich AU - Carme Arnan AU - Rory Johnson AU - Sílvia Pérez-Lluch AU - Roderic Guigó Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/10/29/2021.10.28.466072.abstract N2 - Many developmental and differentiation processes take substantially longer in human than in mouse. To investigate the molecular mechanisms underlying this phenomenon, here we have specifically focused on the transdifferentiation from B cells to macrophages. The process is triggered by exactly the same molecular mechanism -- the induction by the transcription factor (TF) CEBPA -- but takes three days in mouse and seven in human (1, 2). In mouse, the speed of this process is known to be associated with Myc expression (3). We found that in this species, CEBPA binds strongly to the Myc promoter, efficiently down-regulating Myc. In human, in contrast, CEBPA does not bind this promoter, and MYC is indirectly and more slowly down-regulated. Attenuation of CEBPA binding is not specific to the MYC promoter, but a general trait of the human genome across multiple biological conditions. We traced back weak CEBPA binding to the primate-specific Alu repeat expansion. Many Alu repeats carry strong CEBPA binding motifs, which sequester CEBPA, and attenuate CEBPA binding genome-wide. We observed similar CEBPA and MYC dynamics in natural processes regulated by CEBPA, suggesting that CEBPA attenuation could underlie the longer duration in human processes controlled by this factor. Our work highlights the highly complex mode in which biological information is encoded in genome sequences, evolutionarily connecting, in an unexpected way, lineage-specific transposable element expansions to species-specific changes in developmental tempos.Competing Interest StatementThe authors have declared no competing interest. ER -