HMGA2 mediated histone deposition is required for TGFB1 induced transcription

Objectives During transcriptional activation, chromatin undergoes structural changes with the help of various proteins such as chromatin remodeling factors and histone modifiers in order to make the DNA accessible for the transcription factors and RNA polymerase. The replacement of canonical histones by histone variants and deposition of histones are chromatin regulating mechanisms devised by cells to dynamically regulate gene expression [1]. New evidence suggest that TGFB1 induced transcription requires the phosphorylation of H2A.X at serine 139 [2]. Although we have shown that HMGA2 was required for TGFB1 induced transcription, the mechanism underlying our results was still not completely elucidated. Understanding the architectural chromatin changes mediated by HMGA2 is not only required for lung differentiation during embryogenesis, accumulation of HMGA2 in the cell nucleus is associated with malignant transformation and chemoresistance [1, 3].

Results We combined ChIP- and MNase-sequencing analyzing the Hmga2 knock-out mice and found that HMGA2 is required for promoter specific deposition of the histone variant H2A.X. We further demonstrated that the intrinsic lyase activity of HMGA2 is required for this process. Consequently, the promoter specific H2A.X deposition resulted in an accumulation of active RNA Polymerase II at these promoters. Stimulation with TGFB1 resulted in increased expression of those “primed” target genes, whereas cells expressing no Hmga2 where not able to respond.

Conclusions We conclude that HMGA2 “primes” specific genes via histone deposition at promoters that are activated upon TGFB1 stimulation.

• References

• 1 Ozturk N, Singh I, Mehta A, Braun T, Barreto G. Front Cell Dev Biol 2014; 2: 5 doi:10.3389/fcell.2014.00005 eCollection 2014
• 2 Singh I, Ozturk N, Cordero J, Mehta A, Hasan D, Cosentino C, Sebastian C, Krüger M, Looso M, Carraro G, Bellusci S, Seeger W, Braun T, Mostoslavsky R, Barreto G. Cell Res 2015; 25 (07) 837-850 doi:10.1038/cr.2015.67 Epub 2015 Jun 5
• 3 Singh I, Mehta A, Contreras A, Boettger T, Carraro G, Wheeler M, Cabrera-Fuentes HA, Bellusci S, Seeger W, Braun T, Barreto G. BMC Biol 2014; 12: 21 doi:10.1186/1741-7007-12-21