RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression

Labadorf, Adam; Hoss, Andrew G.; Lagomarsino, Valentina N.; Latourelle, Jeanne C.; Hadzi, Tiffany C.; Bregu, Joli; MacDonald, Marcy E.; Gusella, James F.; Chen, Jiang‐Fan; Akbarian, Schahram; Weng, Zhiping; Myers, Richard H.

doi:10.1371/journal.pone.0143563

Cited by 160 publications

(257 citation statements)

References 67 publications

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“…8). 20-30% of the PRC2-target genes that become up-regulated in PRC2-deficient MSNs, including Pou4f1/2, Hand2, Nkx2-5 , Twist1 , Tal1, Wt1 , and numerous Hox genes, significantly overlap with genes that are up-regulated in the postmortem human brains of HD patients 14,16,17 or HD mouse models 46,47 (Supplementary Fig. 8, Supplementary Table 7).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the expression of mutant huntingtin in mouse ES cells or neuronal progenitor cells (NPCs) alters the pattern of genome-wide H3K27me3 distribution in both cell types 15 . The possible link between PRC2 and HD is further supported by the loss of neuronal PRC2/H3K27me3 sites 14 and the up-regulation of some of the PRC2 target genes in the HD affected human brain 14,16,17 . While these studies suggest that the PRC2 might represent a common target of different pathological processes that drive neurodegenerative diseases, the role of the PRC2 in the regulation of neuronal specification, function and survival in the adult brain is not known.…”

Section: Introductionmentioning

confidence: 97%

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Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration

et al. 2016

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Normal brain function depends on the interaction between highly specialized neurons that operate within anatomically and functionally distinct brain regions. Neuronal specification is driven by transcriptional programs that are established during early neuronal development and remain in place in the adult brain. The fidelity of neuronal specification depends on the robustness of the transcriptional program that supports the neuron type-specific gene expression patterns. Here we show that PRC2, which supports neuron specification during differentiation, contributes to the suppression of a transcriptional program that is detrimental for adult neuron function and survival. We show that PRC2 deficiency in striatal neurons leads to the de-repression of selected, predominantly bivalent PRC2 target genes that are dominated by self-regulating transcription factors normally suppressed in these neurons. The transcriptional changes in PRC2-deficient neurons lead to progressive and fatal neurodegeneration in mice. Our results point to a key role of PRC2 in protecting neurons against degeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration

et al. 2016

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“…By contrast, expression of mutated Huntingtin protein in mouse ESCs or NPCs distorts genome-wide patterns of H3K27me3 together with a reduced presence of H3K4me3 at active loci [111]. The potential link between PRC2 and H3K4me3 is further supported by a significant depletion of H3K4me3 in HD-enriched peaks from ChIP-sequencing of neuronal chromatin from prefrontal cortices [109] and the upregulation of some inflammatory and developmental PRC2 target genes, particularly of certain Hox genes, in HD brains [112,113].…”

Section: Polycomb Group Complexes In Mature Neurons and Neurodegeneramentioning

confidence: 98%

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

et al. 2017

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Polycomb Group (PcG) proteins are best-known for maintaining repressive or active chromatin states that are passed on across multiple cell divisions, and thus sustain long-term memory of gene expression. PcG proteins engage different, partly gene-and/or stage-specific, mechanisms to mediate spatiotemporal gene expression during central nervous system development. In the course of this, PcG proteins bind to various cis-regulatory sequences (e.g., promoters, enhancers or silencers) and coordinate, as well the interactions between distantly separated genomic regions to control chromatin function at different scales ranging from compaction of the linear chromatin to the formation of topological hubs. Recent findings show that PcG proteins are involved in switch-like changes in gene expression states of selected neural genes during the transition from multipotent to differentiating cells, and then to mature neurons. Beyond neurodevelopment, PcG proteins sustain mature neuronal function and viability, and prevent progressive neurodegeneration in mice. In support of this view, neuropathological findings from human neurodegenerative diseases point to altered PcG functions. Overall, improved insight into the multiplicity of PcG functions may advance our understanding of human neurodegenerative diseases and ultimately pave the way to new therapies.

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“…Further, our in vitro studies using an embryonic stem cell line carrying mutant huntingtin (mHtt) demonstrates that this protein impairs the specification and maturation of organ-specific cellular lineages, as well as those of region-specific neural cellular subtypes (Nguyen et al, 2013a; Nguyen et al, 2013b). Accordingly, recent transcriptomic studies have reported that genes with key developmental and neural functions are preferentially impacted in specimens carrying mHtt (Achour et al, 2015; Jin et al, 2012; Labadorf et al, 2015; Ng et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

Arteaga-Bracho

Gulinello

Winchester

et al. 2016

Neurobiology of Disease

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The mutation in huntingtin (mHtt) leads to a spectrum of impairments in the developing forebrain of Huntington’s disease (HD) mouse models. Whether these developmental alterations are due to loss- or gain-of-function mechanisms and contribute to HD pathogenesis is unknown. We examined the role of selective loss of huntingtin (Htt) function during development on postnatal vulnerability to cell death. We employed mice expressing very low levels of Htt throughout embryonic life to postnatal day 21 (Hdhd•hyp). We demonstrated that Hdhd•hyp mice exhibit: (1) late-life striatal and cortical neuronal degeneration; (2) neurological and skeletal muscle alterations; and (3) white matter tract impairments and axonal degeneration. Hdhd•hyp embryos also exhibited subpallial heterotopias, aberrant striatal maturation and deregulation of gliogenesis. These results indicate that developmental deficits associated with Htt functions render cells present at discrete neural foci increasingly susceptible to cell death, thus implying the potential existence of a loss-of-function developmental component to HD pathogenesis.

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RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression

Cited by 160 publications

References 67 publications

Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration

Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration

Switch-Like Roles for Polycomb Proteins from Neurodevelopment to Neurodegeneration

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

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