RT Journal Article
SR Electronic
T1 Alu-mediated weak CEBPA binding and slow B cell transdifferentiation in human
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.28.466072
DO 10.1101/2021.10.28.466072
A1 Ramil Nurtdinov
A1 María Sanz
A1 Amaya Abad
A1 Alexandre Esteban
A1 Sebastian Ullrich
A1 Carme Arnan
A1 Rory Johnson
A1 Sílvia Pérez-Lluch
A1 Roderic Guigó
YR 2021
UL http://biorxiv.org/content/early/2021/10/29/2021.10.28.466072.abstract
AB 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.