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Michael Howard

Research Associate Professor of Human Genetics

Decoding the Genome

Mike Howard

 

Molecular Biology Program

Education

B.S. University of Colorado, Boulder

Ph.D. University of North Carolina, Chapel Hill

 

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. Howard MT, Copeland PR. New Directions for Understanding the Codon Redefinition Required for Selenocysteine Incorporation. Biol Trace Elem Res2019 Nov;192(1):18-25doi: 10.1007/s12011-019-01827-y. Epub 2019 Jul 24. Review.
  2. Zhao W, Bohleber S, Schmidt H, Seeher S, Howard MT, Braun D, Arndt S, Reuter U, Wende H, Birchmeier C, Fradejas-Villar N, Schweizer U. Ribosome profiling of selenoproteins in vivo reveals consequences of pathogenic Secisbp2 missense mutations. J Biol Chem2019 Sep 27;294(39):14185-14200doi: 10.1074/jbc.RA119.009369.
  3. Mahmassani ZS, Reidy PT, McKenzie AI, Stubben C, Howard MT, Drummond MJ. Disuse-induced insulin resistance susceptibility coincides with a dysregulated skeletal muscle metabolic transcriptome. J Appl Physiol (1985)2019 May 1;126(5):1419-1429doi: 10.1152/japplphysiol.01093.2018.
  4. Mahmassani ZS, Reidy PT, McKenzie AI, Stubben C, Howard MT, Drummond MJ. Age-dependent skeletal muscle transcriptome response to bed rest-induced atrophy. J Appl Physiol (1985)2019 Apr 1;126(4):894-902doi: 10.1152/japplphysiol.00811.2018.
  5. Dalley BK, Baird L, Howard MT. Studying Selenoprotein mRNA Translation Using RNA-Seq and Ribosome Profiling. Methods Mol Biol2018;1661:103-123doi: 10.1007/978-1-4939-7258-6_8.
  6. Mariotti M, Shetty S, Baird L, Wu S, Loughran G, Copeland PR, Atkins JF, Howard MT. Multiple RNA structures affect translation initiation and UGA redefinition efficiency during synthesis of selenoprotein P. Nucleic Acids Res2017 Dec 15;45(22):13004-13015doi: 10.1093/nar/gkx982.
  7. Drummond MJ, Reidy PT, Baird LM, Dalley BK, Howard MT. Leucine Differentially Regulates Gene-Specific Translation in Mouse Skeletal Muscle. J Nutr2017 Sep;147(9):1616-1623doi: 10.3945/jn.117.251181.
  8. Loughran G, Howard MT, Firth AE, Atkins JF. Avoidance of reporter assay distortions from fused dual reporters. RNA2017 Aug;23(8):1285-1289doi: 10.1261/rna.061051.117. 
  9. Fradejas-Villar N, Seeher S, Anderson CB, Doengi M, Carlson BA, Hatfield DL, Schweizer U, Howard MT. The RNA-binding protein Secisbp2 differentially modulates UGA codon reassignment and RNA decay. Nucleic Acids Res2017 Apr 20;45(7):4094-4107doi: 10.1093/nar/gkw1255.
  10. Gladyshev VN, Arnér ES, Berry MJ, Brigelius-Flohé R, Bruford EA, Burk RF, Carlson BA, Castellano S, Chavatte L, Conrad M, Copeland PR, Diamond AM, Driscoll DM, Ferreiro A, Flohé L, Green FR, Guigó R, Handy DE, Hatfield DL, Hesketh J, Hoffmann PR, Holmgren A, Hondal RJ, Howard MT, Huang K, Kim HY, Kim IY, Köhrle J, Krol A, Kryukov GV, Lee BJ, Lee BC, Lei XG, Liu Q, Lescure A, Lobanov AV, Loscalzo J, Maiorino M, Mariotti M, Sandeep Prabhu K, Rayman MP, Rozovsky S, Salinas G, Schmidt EE, Schomburg L, Schweizer U, Simonović M, Sunde RA, Tsuji PA, Tweedie S, Ursini F, Whanger PD, Zhang Y. Selenoprotein Gene Nomenclature. J Biol Chem2016 Nov 11;291(46):24036-24040doi: 10.1074/jbc.M116.756155.
  11. Wu S, Mariotti M, Santesmasses D, Hill KE, Baclaocos J, Aparicio-Prat E, Li S, Mackrill J, Wu Y, Howard MT, Capecchi M, Guigó R, Burk RF, Atkins JF. Human selenoprotein P and S variant mRNAs with different numbers of SECIS elements and inferences from mutant mice of the roles of multiple SECIS elements. Open Biol2016 Nov;6(11)doi: 10.1098/rsob.160241.
  12. Howard MT. Probing Selenoprotein Translation by Ribosome Profiling . In: Selenium: Its Molecular Biology and Role in Human Health. fourth ed. Hatfield DL, Schweizer U, Tsuji PA, Gladyshev VN, editors. New York: Springer; 2016. Chapter 3; p.25-38.
  13. Tsuji PA, Carlson BA, Anderson CB, Seifried HE, Hatfield DL, Howard MT. Dietary Selenium Levels Affect Selenoprotein Expression and Support the Interferon-γ and IL-6 Immune Response Pathways in Mice. Nutrients2015 Aug 6;7(8):6529-49doi: 10.3390/nu7085297
  14. 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. Clinical phenotypes as predictors of the outcome of skipping around DMD exon 45. Ann Neurol2015 Apr;77(4):668-74doi: 10.1002/ana.24365.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. Fixsen SM, Howard MT (2010) Processive selenocysteine incorporation during synthesis of eukaryotic selenoproteins. J Mol Biol. 399(3):385-96.
  29. 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.
Last Updated: 7/1/21