Carolyn J. Brown

Last updated
Carolyn J. Brown
Alma mater University of Guelph, BA
University of Toronto, PhD
Stanford University, PhD
Scientific career
Fields Human Genetics, Epigenetics, X-inactivation
Academic advisors Hunt Willard
Website Lab webpage
University webpage

Carolyn J. Brown (born in 1961, Ontario) is a Canadian geneticist and Professor in the Department of Medical Genetics at the University of British Columbia. Brown is known for her studies on X-chromosome inactivation, having discovered the human XIST gene in 1990.

Contents

Education and early career

Brown received her Bachelor of Science in Genetics in 1983 from the University of Guelph, Ontario. She started her PhD thesis work at the University of Toronto in 1983, under the supervision of Hunt Willard, and concluded it at Stanford University, following the moving of Willard’s laboratory in 1989. Brown initiated the studies of the X chromosome in the lab, and her PhD thesis was entitled “Studies of Human X-Chromosome Inactivation”. Her work involved the analysis of genes that “escape” X-chromosome inactivation, being expressed from the (otherwise) inactive X chromosome, as well as the molecular characterization of the X-inactivation center, the genetic locus necessary for silencing of the chromosome. These two topics converged in the 1990 discovery of the XIST gene, which localizes to the X-inactivation center and is expressed solely from the inactive X chromosome. This discovery was reported in two papers in Nature in 1991. [1] [2]

Willard has referred to Brown as "the critical individual who transformed the study of X inactivation". [3] Brown became Research Associate in 1990 in the Stanford Department of Genetics, and two years later moved with Willard’s laboratory to the Department of Genetics of Case Western Reserve University, Ohio, where she continued studying the XIST long noncoding RNA. Brown became Assistant Professor (1994) and Associate Professor (1999) in the Department of Medical Genetics of the University of British Columbia, in Vancouver, and was promoted to Professor in 2004. She was the Head of the Department from 2011 to 2014. She has supervised over twenty postdoctoral fellows and graduate students in her laboratory.

Research

Brown’s research is directed to the X-chromosome inactivation process in humans. Her lab has identified critical differences between mouse and human X-chromosome inactivation, such as the absence of paternal X inactivation in human extraembryonic tissues, the higher proportion of human “escapees” and the identification of different regulatory sequences of human XIST and mouse Xist. [4] [5] Her lab has been cataloging escape genes using both expression and DNA methylation analysis r to determine which genes contribute to sex differences in disease susceptibility, and which regions of DNA are susceptible to, or resistant to, epigenetic gene silencing. [6] [7] [8] [9] Since human embryonic stem cells are epigenetically unstable, Brown and colleagues have developed alternative model systems to study human inactivation, including inducible XIST transgenes in human somatic cells, human somatic cell hybrids retaining the active or the inactive X chromosome, and mouse cells with X-linked transgenes of human DNA. [10] Her lab collaborates with other research groups at the B. C. Children’s Hospital and the BC Cancer Agency to investigate the clinical relevance of X-linked inactivation and expression in disease predisposition, cancer progression, and X-linked diseases, chromosome rearrangements and aneuploidies. [11] [12] [13] [14] [15] [16]

Awards and honors

Related Research Articles

Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed or not, depending on whether they are inherited from the mother or the father. Genes can also be partially imprinted. Partial imprinting occurs when alleles from both parents are differently expressed rather than complete expression and complete suppression of one parent's allele. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. In 2014, there were about 150 imprinted genes known in mice and about half that in humans. As of 2019, 260 imprinted genes have been reported in mice and 228 in humans.

<span class="mw-page-title-main">Barr body</span> Form taken by the inactive X chromosome in a female somatic cell

A Barr body or X-chromatin is an inactive X chromosome. In species with XY sex-determination, females typically have two X chromosomes, and one is rendered inactive in a process called lyonization. Errors in chromosome separation can also result in male and female individuals with extra X chromosomes. The Lyon hypothesis states that in cells with multiple X chromosomes, all but one are inactivated early in embryonic development in mammals. The X chromosomes that become inactivated are chosen randomly, except in marsupials and in some extra-embryonic tissues of some placental mammals, in which the X chromosome from the sperm is always deactivated.

Heterochromatin is a tightly packed form of DNA or condensed DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role in the expression of genes. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed; however, according to Volpe et al. (2002), and many other papers since, much of this DNA is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO4 staining reveal that the dense packing is not due to the chromatin.

<span class="mw-page-title-main">Sex-chromosome dosage compensation</span>

Dosage compensation is the process by which organisms equalize the expression of genes between members of different biological sexes. Across species, different sexes are often characterized by different types and numbers of sex chromosomes. In order to neutralize the large difference in gene dosage produced by differing numbers of sex chromosomes among the sexes, various evolutionary branches have acquired various methods to equalize gene expression among the sexes. Because sex chromosomes contain different numbers of genes, different species of organisms have developed different mechanisms to cope with this inequality. Replicating the actual gene is impossible; thus organisms instead equalize the expression from each gene. For example, in humans, female (XX) cells randomly silence the transcription of one X chromosome, and transcribe all information from the other, expressed X chromosome. Thus, human females have the same number of expressed X-linked genes per cell as do human males (XY), both sexes having essentially one X chromosome per cell, from which to transcribe and express genes.

<span class="mw-page-title-main">X-inactivation</span> Inactivation of copies of X chromosome

X-inactivation is a process by which one of the copies of the X chromosome is inactivated in therian female mammals. The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin. As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome.

Huntington Faxon Willard is an American geneticist. In 2014, he was named to head the Marine Biological Laboratory, and is a professor in human genetics at the University of Chicago. He stepped down from leading the lab in 2017 to return to research. Willard was elected to the National Academy of Medicine in 2016. Earlier, beginning in 2003 he was the Nanaline H. Duke Professor of Genome Sciences, the first director of the Institute for Genome Sciences and Policy, and Vice Chancellor for Genome Sciences at Duke University Medical Center in Durham, North Carolina.

<span class="mw-page-title-main">ATR-X syndrome</span> Medical condition

Alpha-thalassemia mental retardation syndrome (ATRX), also called alpha-thalassemia X-linked intellectual disability syndrome, nondeletion type or ATR-X syndrome, is an X-linked recessive condition associated with a mutation in the ATRX gene. Males with this condition tend to be moderately intellectually disabled and have physical characteristics including coarse facial features, microcephaly, hypertelorism, a depressed nasal bridge, a tented upper lip and an everted lower lip. Mild or moderate anemia, associated with alpha-thalassemia, is part of the condition. Females with this mutated gene have no specific signs or features, but if they do, they may demonstrate skewed X chromosome inactivation.

<span class="mw-page-title-main">H2AFY</span> Protein-coding gene in the species Homo sapiens

Core histone macro-H2A.1 is a protein that in humans is encoded by the H2AFY gene.

<span class="mw-page-title-main">XIST</span> Non-coding RNA

Xist is a non-coding RNA on the X chromosome of the placental mammals that acts as a major effector of the X-inactivation process. It is a component of the Xic – X-chromosome inactivation centre – along with two other RNA genes and two protein genes.

<span class="mw-page-title-main">CHD8</span> Protein-coding gene in the species Homo sapiens

Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.

<span class="mw-page-title-main">ZMYM3</span> Protein-coding gene in the species Homo sapiens

Zinc finger MYM-type protein 3 is a protein that in humans is encoded by the ZMYM3 gene.

<span class="mw-page-title-main">Long non-coding RNA</span> Non-protein coding transcripts longer than 200 nucleotides

Long non-coding RNAs are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. Given that some lncRNAs have been reported to have the potential to encode small proteins or micro-peptides, the latest definition of lncRNA is a class of RNA molecules of over 200 nucleotides that have no or limited coding capacity. Long intervening/intergenic noncoding RNAs (lincRNAs) are sequences of lncRNA which do not overlap protein-coding genes.

Skewed X-chromosome inactivation occurs when the X-inactivation of one X chromosome is favored over the other, leading to an uneven number of cells with each chromosome inactivated. It is usually defined as one allele being found on the active X chromosome in over 75% of cells, and extreme skewing is when over 90% of cells have inactivated the same X chromosome. It can be caused by primary nonrandom inactivation, either by chance due to a small cell pool or directed by genes, or by secondary nonrandom inactivation, which occurs by selection.

In molecular biology, FTX transcript, XIST regulator , also known as FTX, is a long non-coding RNA. In humans, it is located on the X chromosome. It was identified during sequence analysis of the X inactivation centre, surrounding the XIST gene. FTX contains several microRNAs within its introns. It upregulates expression of XIST, and inhibits DNA methylation of the XIST promoter.

<span class="mw-page-title-main">Jpx (gene)</span> Non-coding RNA in the species Homo sapiens

In molecular biology, JPX transcript, XIST activator, also known as Jpx, is a long non-coding RNA. In humans, it is located on the X chromosome. It was identified during sequence analysis of the X inactivation centre, surrounding the Xist gene. Jpx upregulates expression of Xist.

<span class="mw-page-title-main">Tsix</span> Non-coding RNA in the species Homo sapiens

Tsix is a non-coding RNA gene that is antisense to the Xist RNA. Tsix binds Xist during X chromosome inactivation. The name Tsix comes from the reverse of Xist, which stands for X-inactive specific transcript.

Epigenetics of human development is the study of how epigenetics effects human development.

<span class="mw-page-title-main">Polycomb recruitment in X chromosome inactivation</span>

X chromosome inactivation (XCI) is the phenomenon that has been selected during the evolution to balance X-linked gene dosage between XX females and XY males.

Jeannie T. Lee is a Professor of Genetics at Harvard Medical School and the Massachusetts General Hospital, and a Howard Hughes Medical Institute Investigator. She is known for her work on X-chromosome inactivation and for discovering the functions of a new class of epigenetic regulators known as long noncoding RNAs (lncRNAs), including Xist and Tsix.

X chromosome reactivation (XCR) is the process by which the inactive X chromosome (the Xi) is re-activated in the cells of eutherian female mammals. Therian female mammalian cells have two X chromosomes, while males have only one, requiring X-chromosome inactivation (XCI) for sex-chromosome dosage compensation. In eutherians, XCI is the random inactivation of one of the X chromosomes, silencing its expression. Much of the scientific knowledge currently known about XCR comes from research limited to mouse models or stem cells.

References

  1. ↑ Brown, Carolyn J.; Ballabio, Andrea; Rupert, James L.; Lafreniere, Ronald G.; Grompe, Markus; Tonlorenzi, Rossana; Willard, Huntington F. (1991). "A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome". Nature. 349 (6304): 38–44. Bibcode:1991Natur.349...38B. doi:10.1038/349038a0. PMID   1985261. S2CID   4332325.
  2. ↑ Brown, Carolyn J.; Lafreniere, Ronald G.; Powers, Vicki E.; Sebastio, Gianfranco; Ballabio, Andrea; Pettigrew, Anjana L.; Ledbetter, David H.; Levy, Elaine; Craig, Ian W.; Willard, Huntington F. (1991). "Localization of the X inactivation centre on the human X chromosome in Xq13". Nature. 349 (6304): 82–84. Bibcode:1991Natur.349...82B. doi:10.1038/349082a0. PMID   1985270. S2CID   4360783.
  3. ↑ Willard, Huntington F. (2010). "2009 William Allan Award Address: Life in the Sandbox: Unfinished Business". The American Journal of Human Genetics. 86 (3): 318–327. doi:10.1016/j.ajhg.2010.01.037. PMC   2833390 .
  4. ↑ Yen, Z. C.; Meyer, I. M.; Karalic, S.; Brown, C. J. (2007). "A cross-species comparison of X-chromosome inactivation in Eutheria". Genomics. 90 (4): 453–63. doi: 10.1016/j.ygeno.2007.07.002 . PMID   17728098.
  5. ↑ Chang, S. C.; Brown, C. J. (2010). "Identification of regulatory elements flanking human XIST reveals species differences". BMC Molecular Biology. 11: 20. doi: 10.1186/1471-2199-11-20 . PMC   2841178 . PMID   20211024.
  6. ↑ Kutsche, R.; Brown, C. J. (2000). "Determination of X-chromosome inactivation status using X-linked expressed polymorphisms identified by database searching". Genomics. 65 (1): 9–15. doi:10.1006/geno.2000.6153. PMID   10777660.
  7. ↑ Cotton, A. M.; Lam, L.; Affleck, J. G.; Wilson, I. M.; Peñaherrera, M. S.; McFadden, D. E.; Kobor, M. S.; Lam, W. L.; Robinson, W. P.; Brown, C. J. (2011). "Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation". Human Genetics. 130 (2): 187–201. doi:10.1007/s00439-011-1007-8. PMC   3132437 . PMID   21597963.
  8. ↑ Cotton, A. M.; Ge, B.; Light, N.; Adoue, V.; Pastinen, T.; Brown, C. J. (2013). "Analysis of expressed SNPs identifies variable extents of expression from the human inactive X chromosome". Genome Biology. 14 (11): R122. doi: 10.1186/gb-2013-14-11-r122 . PMC   4053723 . PMID   24176135.
  9. ↑ Cotton, A. M.; Price, E. M.; Jones, M. J.; Balaton, B. P.; Kobor, M. S.; Brown, C. J. (2015). "Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation". Human Molecular Genetics. 24 (6): 1528–39. doi:10.1093/hmg/ddu564. PMC   4381753 . PMID   25381334.
  10. ↑ Tinker, A. V.; Brown, C. J. (1998). "Induction of XIST expression from the human active X chromosome in mouse/human somatic cell hybrids by DNA demethylation". Nucleic Acids Research. 26 (12): 2935–40. doi:10.1093/nar/26.12.2935. PMC   147638 . PMID   9611238.
  11. ↑ Dawson, A. J.; Wickstrom, D. E.; Riordan, D.; Cardwell, S.; Casey, R.; Baldry, S.; Brown, C. (2004). "A unique patient with an Ullrich-Turner syndrome variant and mosaicism for a tiny r(X) and a partial proximal duplication 1q". American Journal of Medical Genetics. Part A. 124A (3): 303–6. doi:10.1002/ajmg.a.20302. PMID   14708105. S2CID   13408738.
  12. ↑ Gibb, E. A.; Vucic, E. A.; Enfield, K. S.; Stewart, G. L.; Lonergan, K. M.; Kennett, J. Y.; Becker-Santos, D. D.; MacAulay, C. E.; Lam, S.; Brown, C. J.; Lam, W. L. (2011). "Human cancer long non-coding RNA transcriptomes". PLOS ONE. 6 (10): e25915. Bibcode:2011PLoSO...625915G. doi: 10.1371/journal.pone.0025915 . PMC   3185064 . PMID   21991387.
  13. ↑ Cheung, K. J.; Johnson, N. A.; Affleck, J. G.; Severson, T.; Steidl, C.; Ben-Neriah, S.; Schein, J.; Morin, R. D.; Moore, R.; Shah, S. P.; Qian, H.; Paul, J. E.; Telenius, A.; Relander, T.; Lam, W.; Savage, K.; Connors, J. M.; Brown, C.; Marra, M. A.; Gascoyne, R. D.; Horsman, D. E. (2010). "Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis". Cancer Research. 70 (22): 9166–74. doi: 10.1158/0008-5472.CAN-10-2460 . PMID   20884631.
  14. ↑ Johnson, N. A.; Al-Tourah, A.; Brown, C. J.; Connors, J. M.; Gascoyne, R. D.; Horsman, D. E. (2008). "Prognostic significance of secondary cytogenetic alterations in follicular lymphomas". Genes, Chromosomes & Cancer. 47 (12): 1038–48. doi:10.1002/gcc.20606. PMID   18720523. S2CID   20432234.
  15. ↑ Hatakeyama, C.; Anderson, C. L.; Beever, C. L.; Peñaherrera, M. S.; Brown, C. J.; Robinson, W. P. (2004). "The dynamics of X-inactivation skewing as women age". Clinical Genetics. 66 (4): 327–32. doi:10.1111/j.1399-0004.2004.00310.x. PMID   15355435. S2CID   23931974.
  16. ↑ Beever, C. L.; Stephenson, M. D.; Peñaherrera, M. S.; Jiang, R. H.; Kalousek, D. K.; Hayden, M.; Field, L.; Brown, C. J.; Robinson, W. P. (2003). "Skewed X-chromosome inactivation is associated with trisomy in women ascertained on the basis of recurrent spontaneous abortion or chromosomally abnormal pregnancies". American Journal of Human Genetics. 72 (2): 399–407. doi:10.1086/346119. PMC   379232 . PMID   12497247.
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