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Michael Howard

Research Associate Professor of Human Genetics

Mike Howard

B.S. University of Colorado, Boulder

Ph.D. University of North Carolina, Chapel Hill

Research

References

mhoward@genetics.utah.edu

Mike Howard's Lab Page

Mike Howard's PubMed Literature Search

Molecular Biology Program

Decoding the Genome

Research

We study the mechanisms controlling gene expression acting at the level of protein synthesis. Gene expression is a multistep process involving control of both transcription and translation. While much is known regarding the regulation of transcription, our knowledge of translational regulation has lagged behind. Recent research is revealing a level of hidden complexity in which RNA signals and trans-acting factors can alter conventional translation to control protein expression. These findings have significant implications for our understanding of normal gene expression, and importantly, are providing insight into the molecular consequences of genetic mutations which lead to human disease.

Measuring translation across the genome
Current efforts in the lab are focused on analyzing translational activity on a genome-wide scale by taking advantage of recent advances in deep sequencing technology. In this approach, ribosome position and density on each mRNA is measured by isolation and sequencing of ribosome protected mRNA fragments from cells or whole tissues.  The results are revealing a number of novel insights into the role of translation in normal cellular function and disease.

Selenocysteine: The 21st Amino Acid
A recent significant effort in our laboratory is to understand the mechanism by which UGA codons (normally decoded as stop codons) are redefined to encode the amino acid selenocysteine. The selenocysteine residue is a highly reactive amino acid at physiological pH which is often utilized for specific enzymatic reactions. Selenoproteins play a role in many essential biological functions including protection against oxidative damage, production/interconversion of thyroid hormones, and normal muscle development. We are actively investigating the mechanisms of selenocysteine insertion and its regulation using a combination of biochemical, genetic, and cell based methodologies.

Practical Implications
The insight gained from studying these, and other examples, of altered translational control of gene expression are proving useful for the development of innovative small molecule and antisense based therapeutic approaches to suppressing disease causing genetic mutations. By mimicking the natural signals which cause stop codon redefinition, premature stop codon mutations can be “read through” during translation to produce functional full length proteins. Likewise, understanding the translational control mechanisms that contribute to disease pathogenesis identifies novel pathways for developing therapeutic interventions.

References

  1. Wein N, Vulin A, Falzarano MS, Szigyarto CA, Maiti B, Findlay A, Heller KN, Uhlén M, Bakthavachalu B, Messina S, Vita G, Passarelli C, Brioschi S, Bovolenta  M, Neri M, Gualandi F, Wilton SD, Rodino-Klapac LR, Yang L, Dunn DM, Schoenberg DR, Weiss RB, Howard MT, Ferlini A, Flanigan KM (2015) Corrigendum: Translation from a  DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nat Med. 21(5):537.
  2. Wein N, Vulin A, Falzarano MS, Szigyarto CA, Maiti B, Findlay A, Heller KN, Uhlén M, Bakthavachalu B, Messina S, Vita G, Passarelli C, Gualandi F, Wilton SD, Rodino-Klapac LR, Yang L, Dunn DM, Schoenberg DR, Weiss RB, Howard MT, Ferlini A, Flanigan KM (2015) Corrigendum: Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nat Med. 21(4):414.
  3. Findlay AR, Wein N, Kaminoh Y, Taylor LE, Dunn DM, Mendell JR, King WM, Pestronk A, Florence JM, Mathews KD, Finkel RS, Swoboda KJ, Howard MT, Day JW, McDonald C, Nicolas A, Le Rumeur E, Weiss RB, Flanigan KM; United Dystrophinopathy Project (2015) Clinical phenotypes as predictors of the outcome of skipping around DMD exon 45. Ann Neurol. 77(4):668-74.
  4. Wein N, Vulin A, Falzarano MS, Szigyarto CA, Maiti B, Findlay A, Heller KN, Uhlén M, Bakthavachalu B, Messina S, Vita G, Passarelli C, Gualandi F, Wilton SD, Rodino-Klapac LR, Yang L, Dunn DM, Schoenberg DR, Weiss RB, Howard MT, Ferlini A, Flanigan KM (2014) Translation from a DMD exon 5 IRES results in a functional dystrophin isoform that attenuates dystrophinopathy in humans and mice. Nat Med. 20(9):992-1000.
  5. Larsen CA, Howard MT (2014) Conserved regions of the DMD 3' UTR regulate translation and mRNA abundance in cultured myotubes. Neuromuscul Disord. 2014 Aug;24(8):693-706.
  6. Goodenough E, Robinson TM, Zook MB, Flanigan KM, Atkins JF, Howard MT, Eisenlohr LC (2015) Cryptic MHC class I-binding peptides are revealed by aminoglycoside-induced stop codon read-through into the 3' UTR. Proc Natl Acad Sci U S A. 111(15):5670-5.
  7. Vulin A, Wein N, Strandjord DM, Johnson EK, Findlay AR, Maiti B, Howard MT, Kaminoh YJ, Taylor LE, Simmons TR, Ray WC, Montanaro F, Ervasti JM, Flanigan KM (2014) The ZZ domain of dystrophin in DMD: making sense of missense mutations. Hum Mutat. 35(2):257-64.
  8. Howard MT, Carlson BA, Anderson CB, Hatfield DL (2013) Translational redefinition of UGA codons is regulated by selenium availability. J Biol Chem. 288(27):19401-13.
  9. Flanigan KM, Ceco E, Lamar KM, Kaminoh Y, Dunn DM, Mendell JR, King WM, Pestronk A, Florence JM, Mathews KD, Finkel RS, Swoboda KJ, Gappmaier E, Howard MT, Day JW, McDonald C, McNally EM, Weiss RB; United Dystrophinopathy Project (2013) LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy. Ann Neurol. 73(4):481-8.
  10. Flanigan KM, Wein N, Gurvich OL, Howard MT, Weiss RB (2013) Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2.  Neuromuscul Disord. 23(2):192.
  11. Shirts BH, Howard MT, Hasstedt SJ, Nanjee MN, Knight S, Carlquist JF, Anderson JL, Hopkins PN, Hunt SC (2012) Vitamin D dependent effects of APOA5 polymorphisms on HDL cholesterol. Atherosclerosis. 222(1):167-74.
  12. Flanigan KM, Dunn DM, von Niederhausern A, Soltanzadeh P, Howard MT, Sampson  JB, Swoboda KJ, Bromberg MB, Mendell JR, Taylor LE, Anderson CB, Pestronk A, Florence JM, Connolly AM, Mathews KD, Wong B, Finkel RS, Bonnemann CG, Day JW, McDonald C; United Dystrophinopathy Project Consortium, Weiss RB (2011) Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition  and splicing regulatory elements within the DMD gene. Hum Mutat. 32(3):299-308.
  13. Soltanzadeh P, Friez MJ, Dunn D, von Niederhausern A, Gurvich OL, Swoboda KJ, Sampson JB, Pestronk A, Connolly AM, Florence JM, Finkel RS, Bönnemann CG, Medne  L, Mendell JR, Mathews KD, Wong BL, Sussman MD, Zonana J, Kovak K, Gospe SM Jr, Gappmaier E, Taylor LE, Howard MT, Weiss RB, Flanigan KM (2010) Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul Disord. 20(8):499-504.
  14. Fixsen SM, Howard MT (2010) Processive selenocysteine incorporation during synthesis of eukaryotic selenoproteins. J Mol Biol. 399(3):385-96.
  15. Flanigan KM, Dunn DM, von Niederhausern A, Soltanzadeh P, Gappmaier E, Howard MT, Sampson JB, Mendell JR, Wall C, King WM, Pestronk A, Florence JM, Connolly AM, Mathews KD, Stephan CM, Laubenthal KS, Wong BL, Morehart PJ, Meyer A, Finkel  RS, Bonnemann CG, Medne L, Day JW, Dalton JC, Margolis MK, Hinton VJ; United Dystrophinopathy Project Consortium, Weiss RB (2009) Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum Mutat. 30(12):1657-66.

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Last Updated: 11/2/16