促進皮質神經再生過程中的WNT3A基因增強子表觀遺傳修飾及KLF4的抑制效果

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研究生：	張筑芫 Chang, Chu-Yuan
論文名稱：	促進皮質神經再生過程中的WNT3A基因增強子表觀遺傳修飾及KLF4的抑制效果 Epigenetic regulation of enhancer for induced WNT3A and inhibitory effect of KLF4 during regeneration of injured cortical neurons
指導教授：	陳令儀 Chen, Lin-yi
口試委員:	張壯榮 Chang, Chuang-Rung 黃兆祺 Hwang, Eric 楊尚訓 Yang, Shang-Hsun 李宜靜 Lee, Yi-Ching
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2020
畢業學年度：	108
語文別：	英文
論文頁數：	139
中文關鍵詞：	皮質神經細胞元、創傷性腦損傷、增強子、組蛋白修飾、WNT3A蛋白、KLF4轉錄因子、神經再生
外文關鍵詞：	neuronal regeneration, traumatic brain injury, WNT3A, enhancer regulation, histone modification, cortical neurons, klf4
相關次數：	點閱：3 下載：0
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創傷性腦損傷 (TBI) 是一種由外力撞擊或快速頭部晃動所造成的腦組織傷害，並依其嚴重程度可能造成終生失能。根據2019年的預估，每年全球有超過6,900萬人口受TBI所苦。引起TBI的原因已知和國家經濟發展程度、年齡等相關；在已發展國家中，老年人不慎跌倒為引發TBI主要因素，而發展中國家則以交通事故佔多數。然而，由於缺乏對於腦部神經再生機制的了解，目前臨床上並無有效治癒TBI的療法。WNT家族成員配體蛋白 (ligand) 在中樞神經系統發育過程中扮演相當重要的角色，由過去文獻中指出，異常WNT訊息傳遞與神經退化性疾病相關。在本論文前半部，我們比較了受傷的初代皮質神經元於再生過程中數個WNT基因表達量的變化。由於受傷皮質神經元中，WNT3A基因被誘發表達，因此我們分別在體外 (in vitro) 培養初代皮質神經元，以及離體 (ex vivo) 大腦組織切片培養之TBI模式實驗中外加WNT3A重組蛋白，觀察到增加WNT3A有效促進神經軸突再生。根據過去發表的研究指出，TBI 會產生細胞體表觀遺傳基因組重新編程；為了探究WNT3A在皮質神經元再生過程中如何透過表觀遺傳機制進行轉錄調控，我們進行組蛋H3K4me3與H3K27ac的染色質免疫沉澱實驗搭配後續高通量核酸定序 (ChIP-seq)，透過讀值分析、資料集蒐集與訓練、ENCODE ChIP-seq資料庫比對，預測可能調控WNT3A基因表達的增強子 (enhancer) 。實驗結果顯示，受傷初代皮質神經元中調控WNT3A基因表達的增強子在神經再生過程中具有組蛋白H3K4me1標記特徵與eRNA轉錄；利用CRISPR/Cas9基因編輯技術進行增強子刪除顯著抑制由受傷所誘發的WNT3A基因表達。此外，由染色體構象捕獲(3C)實驗結果我們發現，神經再生過程中DNA可能透過3D結構轉化改變增強子-啟動子 (promoter) 交互作用，以促進長距離WNT3A基因轉錄調控。為了向上游進一步鑑定可能調控WNT3A表達的轉錄因子，我們在受傷皮質神經元再生過程中組蛋白H3K27ac標記顯著變化的基因組片段以及WNT3A增強子上進行DNA結構模組 (motif) 分析，顯示目標片段上集聚豐富的KLF4/5鏈結模組。KLF轉錄因子家族 (Krüppel-like factors) 在過去文獻中已知影響中樞神經細胞分化，然而KLF家族成員各自對於受傷皮質神經細胞再生過程中所扮演的角色目前缺乏科學驗證。因此，本論文第二部分主要探討KLF4在受傷皮質神經元再生過程中所扮演的角色。由於KLF4蛋白表現量在皮質神經元再生過程中顯著下降，我們在體外TBI模式實驗中過度表現KLF4基因，顯示皮質神經元軸突再生受到抑制；反之，減少KLF4轉譯 (knockdown) 促進皮質神經元軸突再生。此外，初代皮質神經元中過度表現KLF4基因降低WNT3A基因轉錄；反之，外加WNT3A重組蛋白抑制初代皮質神經元中KLF4蛋白表現。根據實驗結果，我們提出KLF4對於受傷皮質神經元的軸突再生具有抑制效果，並且可能和WNT訊息傳遞進行交互作用。綜合本論文研究結果，我們認為調控WNT3A/KLF4具有成為TBI治療標靶的潛力。

Traumatic brain injury (TBI) is caused by either external mechanical force or rapid displacement of the brain tissue in the skull. The result is severe damage to brain function. There are about 69 million people suffering TBI-caused morbidity and disability every year worldwide, largely from the cases of falls and motor vehicle collisions. There is currently no treatment for TBI because of limited knowledge about the mechanisms underlying neuronal regeneration. WNT ligands and related proteins have been implicated in neurodevelopment in the central nervous system, and aberrant WNT signaling has been associated with neurodegenerative diseases. In the first part of this dissertation, the expression of WNT genes during regeneration of primary injured cortical neurons was examined. Because endogenous expression of WNT3A gene was induced in injured cortical neurons, recombinant WNT3A protein promoted neuronal regeneration using in vitro TBI model. We found the overexpression of WNT3A increased percentage of gap closure as well as neurite length of neurite re-growth Treating injured organotypic brain slices with recombinant WNT3A enhanced neurite re-growth, demonstrating a promising effect of WNT3A protein on neuronal regeneration via ex vivo TBI model. Since TBI is known to reprogram the epigenome, chromatin immunoprecipitation-sequencing of histone H3K27ac and H3K4me3 was performed to address the transcriptional regulation of WNT3A during neuronal regeneration. Enhancer for WNT3A gene expression was identified based on epigenetic marks. CRISPR/Cas9-mediated editing of this region prevented the induction of WNT3A expression in injured cortical neurons. Chromosome conformation capture assays were performed to examine topological change of DNA architecture during regeneration of injured cortical neurons. We identified and characterized an enhancer highly primed with histone H3K4me1 in response to injury and proposed a promoter-enhancer topological transformation model that regulates the WNT3A gene expression. Krüppel-like factors (KLFs) have been reported to modulate neurite outgrowth in retinal ganglion cells and brain neurons, yet the effect of individual KLF member on regeneration of injured cortical neurons has not been clarified. Since the DNA binding motifs for KLF4/5 at the identified WNT3A enhancer and H3K27ac-marked genomic loci were enriched, we examined the expression of KLF4 protein during neuronal regeneration. Overexpression of KLF4 gene in cortical neurons suppressed neurite re-growth while knockdown of KLF4 promoted neurite re-growth. Notably, overexpression of KLF4 gene in cortical neurons diminished WNT3A expression, whereas treating cortical neurons with recombinant WNT3A reduced KLF4 protein level. Finally, knockdown of KLF5 gene increased neurite length during differentiation of cortical neurons. We thus suggest an inhibitory role of KLF4 protein during regeneration of injured cortical neurons, partly through the interplay with WNT signaling. In addition, KLF5 may be functionally redundant or compensatory for KLF4 effect during neuronal regeneration. Together, data from this dissertation suggest WNT3A-KLF4 axis is a potential therapeutic target for TBI.

Abstract    I
中文摘要    III
Acknowledgements    V
Table of contents    IX
Introduction    1
Traumatic brain injury (TBI)    1
Epidemiology    1
Primary injury and secondary injury    2
Diagnosis, treatment and current challenges    2
Regeneration of the injured central nervous system (CNS)    4
Extrinsic inhibitory factors that limit axonal regeneration    4
Intrinsic age-related growth ability of neurons    4
Potential transcription factors that are implicated in neuronal regeneration:          Krüppel-like transcription factors    5
Krüppel-like transcription factor 4 (KLF4)    6
KLF4-mediated signaling cascades that modulate neuronal regeneration    7
Roles of the WNT signaling pathway in the nervous system    8
WNT signaling in the nervous system    8
WNT3A and neuronal regeneration    9
The epigenome during regeneration of the nervous system    10
Epigenetics and axonal regeneration    10
Enhancer, enhancer RNA (eRNA), and gene expression    12
Materials and Methods    14
Animals and ethics approval    14
Reagents    14
DNA constructs    15
In vitro culture of primary neurons, injury/regeneration assay, neurite tracking, immunofluorescence staining and quantification of neurite re-growth    15
ChIP-seq, RNA-seq, and superarray qPCR    17
Data analysis    18
Aggregation plot    18
ChromHMM for enhancer prediction    18
Long-range chromatin interaction prediction    19
ENCODE datasets processing    19
Lentivirus production and concentration    20
ChIP-qPCR, RT-qPCR assays and eRNA quantification    20
Organotypic brain slice culture    21
CRISPR/Cas9 enhancer editing    22
Immunofluorescence imaging for KLF4 in HEK293T cells and cortical neurons    22
Immunoblotting and immunoprecipitation    23
Knockdown of KLF5 in cortical neurons and neurite length assessment    24
Statistical analysis    24
Results    25
Establish in vitro TBI model for assessing regeneration of injured cortical neurons    25
Identification of candidate RAGs for axonal regeneration of cortical neurons    25
Identification of WNT genes as RAGs for axonal regeneration of cortical neurons    26
WNT3A recombinant protein promotes neuronal regeneration    27
Putative enhancer regions for WNTs expression and other RAGs    27
Identification of putative enhancer region for WNT3A expression    29
Enhancer-mediated WNT3A expression through chromosome topological transformation    31
Motif enrichment analysis at putative enhancers    33
KLF4 as an inhibitory factor for axonal regeneration in cortical neurons    34
Limited number of binding partners of KLF4 in primary cortical neurons compared to PNS neurons and other cell types    36
The interplay between KLF4 and WNT signaling    37
KLF5 may be redundant or compensatory to KLF4 function during axonal regeneration of injured cortical neurons    39
Discussion    41
Predominant role of H3K4me1 in enhancer activation for the WNT3A gene    41
Enhancer prediction approaches and the target gene prediction    42
Possible mechanism underlying the inhibitory effect of KLF4 during regeneration of injured cortical neurons    44
Therapeutic strategies for TBI    45
Figures    46
Figure 1. Establish an in vitro TBI model for assessing regeneration of injured cortical neurons.    47
Figure 2. Neurite re-growth of primary cortical neurons in an in vitro TBI model.    48
Figure 3. Identification of candidate RAGs for axonal regeneration of cortical neurons.    50
Figure 4. GO analysis for Cluster 3, 6, and 16.    52
Figure 5. Identification of WNT genes as RAGs for axonal regeneration of cortical neurons.    54
Figure 6. Recombinant WNT3A promotes regeneration of injured cortical neurons and brain tissues.    56
Figure 7. The regulation of injury-induced WNT3A may not be dominated by the promoter.    58
Figure 8. Putative enhancer regions for WNTs expression and other RAGs.    59
Figure 9. Expression of genes that are at the proximity around the putative enhancers.    61
Figure 10. Prediction of putative enhancer region for WNT3A expression.    62
Figure 11. Histone modifications and chromatin accessibility at the e5 and e7 enhancers.    64
Figure 12. H3K27ac modifications at WNT3A enhancer regions during neuronal regeneration.    65
Figure 13. H3K4me1 modifications at WNT3A enhancer regions during neuronal regeneration.    66
Figure 14. Expression of e5/e7/e10 eRNAs and the e5-closest genes.    67
Figure 15. Editing the e5 enhancer region repressed injured-induced expression of WNT3A.    68
Figure 16. Editing the e5 enhancer region did not affect the expression of the e5-closest genes.    70
Figure 17. e5 eRNAs expression in response to WNT3A treatment in injured cortical neurons.    71
Figure 18. Intrachromosomal interaction visualization model at WNT3A and the e2 of human Hi-C data.    72
Figure 19. Intrachromosomal interaction visualization model at the e5 and e7 of human Hi-C data.    74
Figure 20. Models of histone modifications, eRNA, and DNA topological transformation at WNT3A enhancer regions during neuronal regeneration.    76
Figure 21. Motif enrichment analysis at differential H3K27ac-modified genomic regions.    79
Figure 22. Gene expression of potential injury-induced transcription factors.    81
Figure 23. KLF4 localizes in cell bodies and neurites of cortical neurons.    83
Figure 24. Reduced expression of KLF4 protein during regeneration of injured cortical neurons.    84
Figure 25. Overexpression of KLF4 inhibits neurite re-growth of cortical neurons.    87
Figure 26. Knockdown of KLF4 promotes axonal regeneration of cortical neurons.    88
Figure 27. Investigation of binding partners with KLF4 in HEK293T cells and cortical neurons.    90
Figure 28. Investigation of cytokine-induced STAT3-KLF4 interaction.    91
Figure 29. Investigation of the interplay between KLF4 and P300.    92
Figure 30. Acetylation of KLF4 during regeneration of injured cortical neurons.    93
Figure 31. Reduced expression of β-catenin during regeneration of injured cortical neurons.    94
Figure 32. Examination of the interplay between KLF4 and WNT signaling.    95
Figure 33. Knockdown of KLF5 promotes neurite growth in cortical neurons.    96
Figure 34. Working model.    98
Figure 35. Extensive RAG-regulating enhancers prediction.    99
Tables    100
Table 1. WNT signaling in the CNS of rodents during development    100
Table 2. WNT signaling in the CNS injury of rodents    101
Table 3. Identity of homologous enhancers between rat an mouse genome    102
Table 4. Enhancer e5 binding motif analysis    103
Table 5. KLF4 potential target genes    104
Table 6. shRNA, sgRNA sequences    105
Table 7. List of primers used in the study    106
List of the electronic supplementary materials (ESMs)    109
References    110


                                

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