So hush, little baby, don’t you cry/transcribe

“So hush, little baby, don’t you cry” is from the lyrics of Summertime in Porgy and Bess, the first true American opera.  Although first performed in 1935, scandalously it didn’t get its Met performance until 1985.

But HUSH in this context means Human Silencing Hub which keeps invaders into our genome quiet.  One class of invader is the l1 retrotransposon, which comprises 17% of our genome (there are others).  It is not transcribed into mRNA, clearly a good thing.  Unfortunately HUSH will block some attempts at gene therapy (those putting a new gene into our genome, rather than just correcting a mutated one).

HUSH is made from 3 proteins TASOR, MPP8 and periphilin. A great paper (Nature vol. 601 pp. 440 – 445 ’22) shows how it works.  HUSH recruits an ATP dependent chromatin remodeler producing chromosome compaction (so the transcription machinery can’t get to the gene) and SETDB1, which methylates the lysine at position #9 of histone H3.  This modification binds other proteins which further compact DNA.

Why doesn’t HUSH shut everything down?  It appears to recognize transcripts longer than 1.5 kiloBases — typical of L1 which is > 5 kiloBases long.   How HUSH does this isn’t known at present.

Our genes are broken into pieces called exons (average length 237 bases) separated by introns.  L1 and all retrotransposons, don’t have them as they are reverse transcribed from cytoplasmic RNA which has had the introns removed.

So HUSH’s incredible cleverness silences a DNA sequence it (and you) have never heard of, just by its absence of introns.

 

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Comments

  • Peter Shenkin  On January 25, 2022 at 1:15 am

    Actually, “Hush Little Baby, Don’t You Cry” is a bona fide folk song, collected by Cecil Sharp in 1918. Jean Ritchie has a well known version.

    The phrase is also used as the opening line for a song called “All My Trials” (or sometimes, “All My Troubles), which was first recorded in the 1950s. Harry Belafonte recorded an excellent version.

    Neither song was in the original Gershwin show (which I practically memorized as a child, from the record!) but one or the other might possibly have been interpolated into a later production.

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