An open or closed case for HMGA

An open or closed case for HMGA S enescence turns a chromatin-activating protein towards the dark side. Upon senescence induction, high mobility group A (HMGA) protein helps to make silent heterochromatin, report Masashi Narita, Scott Lowe, and colleagues (Cold Spring Harbor Laboratory, NY). HMGA proteins promote open and active chromatin, are highly expressed in the early embryo, and can promote tumorigenesis. But the new results now show that HMGA is also found in senescent cells, which—in stark contrast to embryonic or tumor cells—no longer respond to mitogenic stimuli. Senescent cells often form dense nuclear chromatin blobs called senescence-associated heterochromatic foci (SAHF), which the Lowe lab fi rst described three years ago. While working to determine the chromatin components and epigenetic modifi cations that characterize SAHFs, they found that HMGA was upregulated in senescent cells. Its previously diffuse nuclear distribution in normal cells became a punctate pattern, as HMGA colocalized at SAHFs with the HP1 heterochromatin protein. HMGA does not just passively associate with SAHFs; knock down of HMGA revealed that it is needed both to establish and maintain SAHFs. The transcriptional repression of multiple genes, including cell cycle factors, also depended on HMGA. How can HMGA switch between such opposite roles? Evidence suggests that HMGA can be phosphorylated, acetylated, and methylated at specifi c amino acids. Acetylation, at least, has been shown to alter HMGA’s transcriptional activity. It is therefore possible that, just as the chromosomal histones are modifi ed to either condense or open chromatin, so too is HMGA.