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Evidence for transcriptional factor dysregulation in the dorsal raphe nucleus of patients with major depressive disorder.

Kerman IA, Bernard R, Bunney WE, Jones EG, Schatzberg AF, Myers RM, Barchas JD, Akil H, Watson SJ, Thompson RC - Front Neurosci (2012)

Bottom Line: Extracted RNA was prepared for gene expression profiling, and subsequent confirmation of select targets with quantitative real-time PCR.These observations indicate altered function of several transcriptional regulators and their downstream targets, which may lead to the dysregulation of multiple cellular functions that contribute to the pathophysiology of MDD.Future studies will require single cell analyses in the DR to determine potential impact of these changes on its cellular functions and related circuits.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham Birmingham, AL, USA.

ABSTRACT
Extensive evidence implicates dysfunction in serotonin (5-HT) signaling in the etiology of major depressive disorder (MDD). Dorsal raphe nucleus (DR) is a major source of serotonin in the brain, and previous studies have reported within it alterations in 5-HT-related gene expression, protein levels, receptor binding, and morphological organization in mood disorders. In the present study, we utilized in situ hybridization-guided laser capture microdissection to harvest tissue samples from the middle-caudal subregion of the human DR post-mortem from MDD patients and from psychiatrically normal comparison subjects. Extracted RNA was prepared for gene expression profiling, and subsequent confirmation of select targets with quantitative real-time PCR. Our data indicate expression changes in functional gene families that regulate: (1) cellular stress and energy balance, (2) intracellular signaling and transcriptional regulation, and (3) cell proliferation and connectivity. The greatest changes in expression were observed among transcriptional regulators, including downregulation in the expression of TOB1, EGR1, and NR4A2 and their downstream targets. Previous studies have implicated these gene products in the regulation of functional domains impacted by MDD, including cognitive function, affective regulation, and emotional memory formation. These observations indicate altered function of several transcriptional regulators and their downstream targets, which may lead to the dysregulation of multiple cellular functions that contribute to the pathophysiology of MDD. Future studies will require single cell analyses in the DR to determine potential impact of these changes on its cellular functions and related circuits.

No MeSH data available.


Related in: MedlinePlus

Downstream gene targets of TOB1, EGR1, and NR4A2 that were altered in their expression in the MDD group as compared to the C group. Genes were included in this analysis if: (1) they were detected in ≥50% of arrays in either the MDD or C group, (2) their changes in expression were ≥1.1- or ≤−1.1-fold in magnitude, and (3) associated p-values < 0.05. Gene-gene interactions were analyzed using Ingenuity Pathway Analysis knowledge database. Marked in red are gene products that were upregulated, while those in green were downregulated.
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Figure 3: Downstream gene targets of TOB1, EGR1, and NR4A2 that were altered in their expression in the MDD group as compared to the C group. Genes were included in this analysis if: (1) they were detected in ≥50% of arrays in either the MDD or C group, (2) their changes in expression were ≥1.1- or ≤−1.1-fold in magnitude, and (3) associated p-values < 0.05. Gene-gene interactions were analyzed using Ingenuity Pathway Analysis knowledge database. Marked in red are gene products that were upregulated, while those in green were downregulated.

Mentions: Using IPA functional networks feature, we extended our analysis to downstream targets of TOB1, NR4A2, and EGR1. Genes were included in this analysis if they were detected in ≥50% of C or MDD microarrays and were altered in their expression by 1.1-fold or greater at the level of p < 0.05. In the case of TOB1, this analysis revealed a downregulation of SMAD2-SMAD4-TOB and SMAD3-SMAD4-TOB transcriptional regulation complexes along with the downregulation of CCNE2, a cell cycle regulator that belongs to the Cyclin E complex (Figure 3). Expression of multiple genes was downregulated downstream of EGR1, including that of: CCND2, CSDA (which has a reciprocal relationship with EGR1), GADD45B, PPP1R3C, and THRB. Additionally, expression of CHGA, THRA, ALOX5, and CDKN1C was upregulated downstream from EGR1. In the case of NR4A2, its downstream targets of ADM and NR4A3 were downregulated, while CDKN1C and SLC6A3 were upregulated. Interestingly, NR4A3 exhibits a reciprocal relationship with NR4A2, while CDKN1C expression is regulated by both NR4A2 and EGR1 (Figure 3).


Evidence for transcriptional factor dysregulation in the dorsal raphe nucleus of patients with major depressive disorder.

Kerman IA, Bernard R, Bunney WE, Jones EG, Schatzberg AF, Myers RM, Barchas JD, Akil H, Watson SJ, Thompson RC - Front Neurosci (2012)

Downstream gene targets of TOB1, EGR1, and NR4A2 that were altered in their expression in the MDD group as compared to the C group. Genes were included in this analysis if: (1) they were detected in ≥50% of arrays in either the MDD or C group, (2) their changes in expression were ≥1.1- or ≤−1.1-fold in magnitude, and (3) associated p-values < 0.05. Gene-gene interactions were analyzed using Ingenuity Pathway Analysis knowledge database. Marked in red are gene products that were upregulated, while those in green were downregulated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475304&req=5

Figure 3: Downstream gene targets of TOB1, EGR1, and NR4A2 that were altered in their expression in the MDD group as compared to the C group. Genes were included in this analysis if: (1) they were detected in ≥50% of arrays in either the MDD or C group, (2) their changes in expression were ≥1.1- or ≤−1.1-fold in magnitude, and (3) associated p-values < 0.05. Gene-gene interactions were analyzed using Ingenuity Pathway Analysis knowledge database. Marked in red are gene products that were upregulated, while those in green were downregulated.
Mentions: Using IPA functional networks feature, we extended our analysis to downstream targets of TOB1, NR4A2, and EGR1. Genes were included in this analysis if they were detected in ≥50% of C or MDD microarrays and were altered in their expression by 1.1-fold or greater at the level of p < 0.05. In the case of TOB1, this analysis revealed a downregulation of SMAD2-SMAD4-TOB and SMAD3-SMAD4-TOB transcriptional regulation complexes along with the downregulation of CCNE2, a cell cycle regulator that belongs to the Cyclin E complex (Figure 3). Expression of multiple genes was downregulated downstream of EGR1, including that of: CCND2, CSDA (which has a reciprocal relationship with EGR1), GADD45B, PPP1R3C, and THRB. Additionally, expression of CHGA, THRA, ALOX5, and CDKN1C was upregulated downstream from EGR1. In the case of NR4A2, its downstream targets of ADM and NR4A3 were downregulated, while CDKN1C and SLC6A3 were upregulated. Interestingly, NR4A3 exhibits a reciprocal relationship with NR4A2, while CDKN1C expression is regulated by both NR4A2 and EGR1 (Figure 3).

Bottom Line: Extracted RNA was prepared for gene expression profiling, and subsequent confirmation of select targets with quantitative real-time PCR.These observations indicate altered function of several transcriptional regulators and their downstream targets, which may lead to the dysregulation of multiple cellular functions that contribute to the pathophysiology of MDD.Future studies will require single cell analyses in the DR to determine potential impact of these changes on its cellular functions and related circuits.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham Birmingham, AL, USA.

ABSTRACT
Extensive evidence implicates dysfunction in serotonin (5-HT) signaling in the etiology of major depressive disorder (MDD). Dorsal raphe nucleus (DR) is a major source of serotonin in the brain, and previous studies have reported within it alterations in 5-HT-related gene expression, protein levels, receptor binding, and morphological organization in mood disorders. In the present study, we utilized in situ hybridization-guided laser capture microdissection to harvest tissue samples from the middle-caudal subregion of the human DR post-mortem from MDD patients and from psychiatrically normal comparison subjects. Extracted RNA was prepared for gene expression profiling, and subsequent confirmation of select targets with quantitative real-time PCR. Our data indicate expression changes in functional gene families that regulate: (1) cellular stress and energy balance, (2) intracellular signaling and transcriptional regulation, and (3) cell proliferation and connectivity. The greatest changes in expression were observed among transcriptional regulators, including downregulation in the expression of TOB1, EGR1, and NR4A2 and their downstream targets. Previous studies have implicated these gene products in the regulation of functional domains impacted by MDD, including cognitive function, affective regulation, and emotional memory formation. These observations indicate altered function of several transcriptional regulators and their downstream targets, which may lead to the dysregulation of multiple cellular functions that contribute to the pathophysiology of MDD. Future studies will require single cell analyses in the DR to determine potential impact of these changes on its cellular functions and related circuits.

No MeSH data available.


Related in: MedlinePlus