(2019) Development "The people behind the papers - Eduardo Leyva-Diaz and Oliver Hobert."

[Development, 2019]

Transcriptional autoregulation occurs when transcription factors bind their own <i>cis</i>-regulatory sequences, ensuring their own continuous expression along with expression of other targets. During development, continued expression of identity-specifying transcription factors can be achieved by autoregulation, but until now formal evidence for a developmental requirement of autoregulation has been lacking. A new paper in Development provides this proof with the help of CRISPR/Cas9 gene editing in the <i>C. elegans</i> nervous system<i>.</i> We caught up with the paper's two authors: postdoc Eduardo Leyva-Diaz and his supervisor Oliver Hobert, Professor of Biological Sciences and HHMI Investigator at Columbia University, New York, to find out more about the work.

Nakamura S et al. (2016) Nat Commun "Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals."

Nakamura K, Nakamura S, Templer SE, Klein C, Jager PS, Antebi A, Horikawa M, Dieterich C, Latza C, Karalay O

[Nat Commun, 2016]

Germline removal provokes longevity in several species and shifts resources towards survival and repair. Several Caenorhabditis elegans transcription factors regulate longevity arising from germline removal; yet, how they work together is unknown. Here we identify a Myc-like HLH transcription factor network comprised of Mondo/Max-like complex (MML-1/MXL-2) to be required for longevity induced by germline removal, as well as by reduced TOR, insulin/IGF signalling and mitochondrial function. Germline removal increases MML-1 nuclear accumulation and activity. Surprisingly, MML-1 regulates nuclear localization and activity of HLH-30/TFEB, a convergent regulator of autophagy, lysosome biogenesis and longevity, by downregulating TOR signalling via LARS-1/leucyl-transfer RNA synthase. HLH-30 also upregulates MML-1 upon germline removal. Mammalian MondoA/B and TFEB show similar mutual regulation. MML-1/MXL-2 and HLH-30 transcriptomes show both shared and preferential outputs including MDL-1/MAD-like HLH factor required for longevity. These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival.

Pierce SB et al. (2013) Am J Hum Genet "Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome."

Klevit RE, Pierce SB, Walsh T, Malach D, Michaelson-Cohen R, Lee MK, Gersak K, King MC, Levy-Lahad E

[Am J Hum Genet, 2013]

The genetic causes of premature ovarian failure (POF) are highly heterogeneous, and causative mutations have been identified in more than ten genes so far. In two families affected by POF accompanied by hearing loss (together, these symptoms compose Perrault syndrome), exome sequencing revealed mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase: homozygous c.1565C&gt;A (p.Thr522Asn) in a consanguineous Palestinian family and compound heterozygous c.1077delT and c.1886C&gt;T (p.Thr629Met) in a nonconsanguineous Slovenian family. LARS2 c.1077delT leads to a frameshift at codon 360 of the 901 residue protein. LARS2 p.Thr522Asn occurs in the LARS2 catalytic domain at a site conserved from bacteria through mammals. LARS2 p.Thr629Met occurs in the LARS2 leucine-specific domain, which is adjacent to a catalytic loop critical in all species but for which primary sequence is not well conserved. A recently developed method of detecting remote homologies revealed threonine at this site in consensus sequences derived from multiple-species alignments seeded by human and E.coli residues at this region. Yeast complementation indicated that LARS2 c.1077delT is nonfunctional and that LARS2 p.Thr522Asn is partially functional. LARS2 p.Thr629Met was functional in this assay but might be insufficient as a heterozygote with the fully nonfunctional LARS2 c.1077delT allele. A known C.elegans strain with the protein-truncating alteration LARS-2 p.Trp247Ter was confirmed to be sterile. After HARS2, LARS2 is the second gene encoding mitochondrial tRNA synthetase to be found to harbor mutations leading to Perrault syndrome, further supportinga critical role for mitochondria in the maintenance of ovarian function and hearing.