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The heterogeneity of microglial activation and its epigenetic and non-coding RNA regulations in the immunopathogenesis of neurodegenerative diseases

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Abstract

Microglia are resident immune cells in the brain and play a central role in the development and surveillance of the nervous system. Extensive gliosis is a common pathological feature of several neurodegenerative diseases, such as Alzheimer's disease (AD), the most common cause of dementia. Microglia can respond to multiple inflammatory insults and later transform into different phenotypes, such as pro- and anti-inflammatory phenotypes, thereby exerting different functions. In recent years, an increasing number of studies based on both traditional bulk sequencing and novel single-cell/nuclear sequencing and multi-omics analysis, have shown that microglial phenotypes are highly heterogeneous and dynamic, depending on the severity and stage of the disease as well as the particular inflammatory milieu. Thus, redirecting microglial activation to beneficial and neuroprotective phenotypes promises to halt the progression of neurodegenerative diseases. To this end, an increasing number of studies have focused on unraveling heterogeneous microglial phenotypes and their underlying molecular mechanisms, including those due to epigenetic and non-coding RNA modulations. In this review, we summarize the epigenetic mechanisms in the form of DNA and histone modifications, as well as the general non-coding RNA regulations that modulate microglial activation during immunopathogenesis of neurodegenerative diseases and discuss promising research approaches in the microglial era.

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Abbreviations

5-azaC:

5-Azacytidine

5-caC:

5-Carboxylcytosine

5-fC:

5-Formylcytosine

5-hmC:

5-Hydroxymethylcytosine

5-mC:

5-Methylcytosine

AAV:

Adeno-associated virus

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

ARG1:

Arginase 1

Aβ:

β-Amyloid peptide

BBB:

Blood–brain barrier

BDNF:

Brain-derived neurotrophic factor

BET:

Bromodomain and extraterminal domain

circRNAs:

Circular RNAs

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DA:

Dopaminergic

DAM:

Disease-associated microglia

DAMPs:

Damage-associated molecular patterns

DHEA:

Dehydroepiandrosterone

DNMTs:

DNA methyltransferases

EAE:

Experimental autoimmune encephalomyelitis

EVs:

Extracellular vesicles

EZH2:

Zeste homolog-2

FTO:

Fat mass and obesity-associated protein

GF:

Germ-free

GWAS:

Genome-wide association studies

H3K27:

Histone H3 at lysine 27

H3S10phK14ac:

Phospho(S10)-acetylation(K14) of histone H3

HD:

Huntington’s disease

HDACs:

Histone deacetylases

HMC3:

Human Microglia Clone 3

HMT:

Histone methyltransferase

hPSCs:

Human pluripotent stem cells

iMGs:

IPSCs-derived microglia

iPSCs:

Induced pluripotent stem cells

JMJD3:

Jumonji domain-containing 3

LDAM:

Lipid droplet-accumulating microglia

lncRNAs:

Long non-coding RNAs

Lnc-SNHG1:

LncRNA small nucleolar RNA host gene 1

LOAD:

Late-onset Alzheimer’s disease

m6A:

N6-methyladenosine

m6Am:

N6,2′-O-dimethyladenosine

MeCP2:

Methyl-CpG binding protein 2

METTL3:

Methyltransferase-like protein 3

MGnD:

Microglial neurodegenerative phenotype

MHC-II:

Major histocompatibility complex II

mHTT:

Mutant huntingtin

miRNAs:

MicroRNAs

MS:

Multiple sclerosis

NAMPs:

Neurodegeneration-associated molecular patterns

NF-κB:

Nuclear factor kappa-B

NRF2:

Nuclear factor erythroid 2-related factor 2

OXPHOS:

Oxidative phosphorylation

PAM:

Plaque-associated microglia

PAMPs:

Pathogen-associated molecular patterns

PD:

Parkinson's disease

PET:

Positron emission tomography

PRC2:

Polycomb repressive complex-2

PSCs:

Pluripotent stem cells

RACK1:

Receptor for activated c kinase 1

RBPs:

RNA binding proteins

rmTBI:

Repetitive mild TBI

ROS:

Reactive oxygen species

SAH:

S-Adenosylhomocysteine

SIRT1:

Sirtuin 1

SN:

Substantia nigra

SNHG1:

Small nucleolar RNA host gene 1

SOCS-1:

Suppressor of cytokine signaling 1

SPF:

Specific-pathogen-free

TBI:

Traumatic brain injury

TDP43:

TAR DNA-binding protein 43

TEM:

Transmission electron microscopy

TET:

Ten-eleven translocation

TREM2:

Triggering receptor expressed on myeloid cells 2

TSA:

Trichostatin A

TSPO:

18 KDa Translocator protein

TSS:

Transcriptional start sites

VPA:

Valproic acid

WAM:

White matter-associated microglia

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Acknowledgements

We apologize to the authors whose work might have been unintentionally omitted due to space limitations. We would like to thank Dr. Hao Deng from the third Xiangya Hospital of Central South University for providing helpful discussions.

Funding

This study was funded by the National Key R&D Program of China [No. 2022ZD0213700], National Natural Sciences Foundation of China [No. 81801200 to YT; 81901223 to FY], Hunan Provincial Natural Science Foundation of China [No. 2019JJ40476 to YT; 2022JJ40824 to JW], Talents Startup Fund [No. 2209090550 to YT] and Youth Science Foundation [No. 2021Q04 to JW] of Xiangya Hospital, Central South University, Changsha, China.

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Authors and Affiliations

  1. Aging Research Center, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Chaoyi Li, Jie Ren, Mengfei Zhang, Huakun Wang, Fang Yi & Yu Tang

  2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Chaoyi Li, Jie Ren, Mengfei Zhang, Huakun Wang, Fang Yi, Junjiao Wu & Yu Tang

  3. Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, 410008, China

    Junjiao Wu

  4. Provincial Clinical Research Center for Rheumatic and Immunologic Diseases, Xiangya Hospital, Central South University, Changsha, 410008, China

    Junjiao Wu

  5. Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Yu Tang

  6. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, 410008, Hunan, China

    Yu Tang

  7. The Biobank of Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Yu Tang

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  1. Chaoyi Li
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  5. Fang Yi
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Contributions

YT conceived this study. CL and YT prepared the draft and figures. YT, CL, JR, MZ, HW, FY and JW discussed and revised the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Yu Tang.

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Li, C., Ren, J., Zhang, M. et al. The heterogeneity of microglial activation and its epigenetic and non-coding RNA regulations in the immunopathogenesis of neurodegenerative diseases. Cell. Mol. Life Sci. 79, 511 (2022). https://doi.org/10.1007/s00018-022-04536-3

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