University of California, Los Angeles

Author Of 1 Presentation

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PS12.03 - Sex Chromosomes in MS Susceptibility

Speakers
Authors
Presentation Number
PS12.03
Presentation Topic
Invited Presentations
Lecture Time
09:45 - 10:00

Abstract

Abstract

Sex differences in MS susceptibility entail women having MS at a rate two to three fold higher than in men. Other autoimmune diseases also show a female preponderance. Sex differences can be due to sex hormones or sex chromosomes or both. Here, we will focus on the role of sex chromosomes. Most Y genes have been lost over evolution with conservation primarily of genes critical for reproduction, while in contrast many X genes are expressed in the immune system or brain. Thus, we focused on the X chromosome. Sex differences in disease susceptibility can be caused an X-dosage effect of X genes that escape X-inactivation or differences in parental imprinting of X genes that do not escape X-inactivation.

Investigate two possible X chromosome gene effects on CD4+ T lymphocytes: 1) an X-dosage effect of X genes that escape X-inactivation and 2) differences in parental imprinting of X genes that do not escape X-inactivation.

Selective deletion of X chromosome genes in CD4+ T lymphocytes, genome-wide transcriptome studies in CD4+ T lymphocytes to determine loss of function effects during selective gene deletion, methylome studies to determine parental imprinting effects.

Regarding X dosage, we found that Kdm6a, a histone demethylase gene that escapes X-inactivation, is expressed higher in CD4+ T lymphocytes of females (XX) than males (XY) in both mice and humans. Selective deletion of Kdm6a from CD4+ T lymphocytes reduced EAE clinical scores and CNS inflammation. The transcriptome of selective Kdm6a knock outs showed decreased neuroinflammatory pathway signaling. Together this demonstrated that Kdm6a expressed at increased dosage in females mediates increased neuroinflammation through Kdm6a’s effect on genome-wide methylation. Regarding parental imprinting of genes that do not escape X-inactivation, we showed that the XY genotype compared to XX, had increased expression of X genes in CD4+ T lymphocytes. Methylation studies revealed that the paternal X chromosome was more methylated than the maternal X chromosome and that paternal X genes had less expression than maternal X genes. Since all cells in males have their X chromosome of maternal origin (XmY), while in females half are of maternal or paternal origin (XmXp), sex differences in parental imprinting explain how X genes that do not escape X-inactivation are expressed less in females than males.

Both an X-dosage effect of X genes that escape X-inactivation and a parental imprinting effect on X genes that undergo X-inactivation occur in CD4+ T lymphocytes to underlie sex differences in autoimmunity.

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Presenter Of 1 Presentation

Invited Presentations Invited Abstracts

PS12.03 - Sex Chromosomes in MS Susceptibility

Speakers
Authors
Presentation Number
PS12.03
Presentation Topic
Invited Presentations
Lecture Time
09:45 - 10:00

Abstract

Abstract

Sex differences in MS susceptibility entail women having MS at a rate two to three fold higher than in men. Other autoimmune diseases also show a female preponderance. Sex differences can be due to sex hormones or sex chromosomes or both. Here, we will focus on the role of sex chromosomes. Most Y genes have been lost over evolution with conservation primarily of genes critical for reproduction, while in contrast many X genes are expressed in the immune system or brain. Thus, we focused on the X chromosome. Sex differences in disease susceptibility can be caused an X-dosage effect of X genes that escape X-inactivation or differences in parental imprinting of X genes that do not escape X-inactivation.

Investigate two possible X chromosome gene effects on CD4+ T lymphocytes: 1) an X-dosage effect of X genes that escape X-inactivation and 2) differences in parental imprinting of X genes that do not escape X-inactivation.

Selective deletion of X chromosome genes in CD4+ T lymphocytes, genome-wide transcriptome studies in CD4+ T lymphocytes to determine loss of function effects during selective gene deletion, methylome studies to determine parental imprinting effects.

Regarding X dosage, we found that Kdm6a, a histone demethylase gene that escapes X-inactivation, is expressed higher in CD4+ T lymphocytes of females (XX) than males (XY) in both mice and humans. Selective deletion of Kdm6a from CD4+ T lymphocytes reduced EAE clinical scores and CNS inflammation. The transcriptome of selective Kdm6a knock outs showed decreased neuroinflammatory pathway signaling. Together this demonstrated that Kdm6a expressed at increased dosage in females mediates increased neuroinflammation through Kdm6a’s effect on genome-wide methylation. Regarding parental imprinting of genes that do not escape X-inactivation, we showed that the XY genotype compared to XX, had increased expression of X genes in CD4+ T lymphocytes. Methylation studies revealed that the paternal X chromosome was more methylated than the maternal X chromosome and that paternal X genes had less expression than maternal X genes. Since all cells in males have their X chromosome of maternal origin (XmY), while in females half are of maternal or paternal origin (XmXp), sex differences in parental imprinting explain how X genes that do not escape X-inactivation are expressed less in females than males.

Both an X-dosage effect of X genes that escape X-inactivation and a parental imprinting effect on X genes that undergo X-inactivation occur in CD4+ T lymphocytes to underlie sex differences in autoimmunity.

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Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

PS12.03 - Sex Chromosomes in MS Susceptibility

Speakers
Authors
Presentation Number
PS12.03
Presentation Topic
Invited Presentations
Lecture Time
09:45 - 10:00

Abstract

Abstract

Sex differences in MS susceptibility entail women having MS at a rate two to three fold higher than in men. Other autoimmune diseases also show a female preponderance. Sex differences can be due to sex hormones or sex chromosomes or both. Here, we will focus on the role of sex chromosomes. Most Y genes have been lost over evolution with conservation primarily of genes critical for reproduction, while in contrast many X genes are expressed in the immune system or brain. Thus, we focused on the X chromosome. Sex differences in disease susceptibility can be caused an X-dosage effect of X genes that escape X-inactivation or differences in parental imprinting of X genes that do not escape X-inactivation.

Investigate two possible X chromosome gene effects on CD4+ T lymphocytes: 1) an X-dosage effect of X genes that escape X-inactivation and 2) differences in parental imprinting of X genes that do not escape X-inactivation.

Selective deletion of X chromosome genes in CD4+ T lymphocytes, genome-wide transcriptome studies in CD4+ T lymphocytes to determine loss of function effects during selective gene deletion, methylome studies to determine parental imprinting effects.

Regarding X dosage, we found that Kdm6a, a histone demethylase gene that escapes X-inactivation, is expressed higher in CD4+ T lymphocytes of females (XX) than males (XY) in both mice and humans. Selective deletion of Kdm6a from CD4+ T lymphocytes reduced EAE clinical scores and CNS inflammation. The transcriptome of selective Kdm6a knock outs showed decreased neuroinflammatory pathway signaling. Together this demonstrated that Kdm6a expressed at increased dosage in females mediates increased neuroinflammation through Kdm6a’s effect on genome-wide methylation. Regarding parental imprinting of genes that do not escape X-inactivation, we showed that the XY genotype compared to XX, had increased expression of X genes in CD4+ T lymphocytes. Methylation studies revealed that the paternal X chromosome was more methylated than the maternal X chromosome and that paternal X genes had less expression than maternal X genes. Since all cells in males have their X chromosome of maternal origin (XmY), while in females half are of maternal or paternal origin (XmXp), sex differences in parental imprinting explain how X genes that do not escape X-inactivation are expressed less in females than males.

Both an X-dosage effect of X genes that escape X-inactivation and a parental imprinting effect on X genes that undergo X-inactivation occur in CD4+ T lymphocytes to underlie sex differences in autoimmunity.

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