The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression.

Jad N Kanbar, Shengyun Ma, Eleanor S Kim, Nadia S Kurd, Matthew S Tsai, Tiffani Tysl, Christella E Widjaja, Abigail E Limary, Brian Yee, Zhaoren He, Yajing Hao, Xiang-Dong Fu, Gene W Yeo, Wendy J Huang, John T Chang

The Journal of experimental medicine · 2022 · Vol. 219 (6)

PubMed DOI PMC Full Text

Abstract

During an immune response to microbial infection, CD8+ T cells give rise to short-lived effector cells and memory cells that provide sustained protection. Although the transcriptional programs regulating CD8+ T cell differentiation have been extensively characterized, the role of long noncoding RNAs (lncRNAs) in this process remains poorly understood. Using a functional genetic knockdown screen, we identified the lncRNA Malat1 as a regulator of terminal effector cells and the terminal effector memory (t-TEM) circulating memory subset. Evaluation of chromatin-enriched lncRNAs revealed that Malat1 grouped with trans lncRNAs that exhibit increased RNA interactions at gene promoters and gene bodies. Moreover, we observed that Malat1 was associated with increased H3K27me3 deposition at a number of memory cell-associated genes through a direct interaction with Ezh2, thereby promoting terminal effector and t-TEM cell differentiation. Our findings suggest an important functional role of Malat1 in regulating CD8+ T cell differentiation and broaden the knowledge base of lncRNAs in CD8+ T cell biology.

Publication Types

["Journal Article", "Research Support, N.I.H., Extramural", "Research Support, U.S. Gov't, Non-P.H.S."]

Keywords

[]

MeSH Terms

["CD8-Positive T-Lymphocytes", "Cell Differentiation", "Epigenetic Repression", "Lymphocyte Activation", "RNA, Long Noncoding"]

Funding

S10 OD026929 NIH HHS (United States)

R01 HG004659 NHGRI NIH HHS (United States)

P30 CA023100 NCI NIH HHS (United States)

P30 DK120515 NIDDK NIH HHS (United States)

R01 AI129973 NIAID NIH HHS (United States)

P01 AI132122 NIAID NIH HHS (United States)

P30 NS047101 NINDS NIH HHS (United States)

R01 AI123202 NIAID NIH HHS (United States)

R01 GM124494 NIGMS NIH HHS (United States)

I01 BX005106 BLRD VA (United States)

R56 DK098808 NIDDK NIH HHS (United States)

R01 DK098808 NIDDK NIH HHS (United States)

P30KC063491 NIH HHS (United States)

P30DK120515 San Diego Digestive Diseases Research Center

Linked Datasets (5)

GSE203092 GSE via ncbi_elink

GEO

The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression

Mus musculus

GSE203086 GSE via ncbi_elink

GEO

The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression (scRNA-Seq)

Mus musculus

17 data files

File	Type	Size
Day_7_Control_1_S17_L008_R1_001.fastq.gz	RNA-Seq	495.0 MB
Day_7_Control_1_S18_L008_R1_001.fastq.gz	RNA-Seq	532.6 MB
Day_7_Control_1_S19_L008_R1_001.fastq.gz	RNA-Seq	778.9 MB
Day_7_Control_1_S20_L008_R1_001.fastq.gz	RNA-Seq	445.9 MB
Day_7_Control_2_S25_L008_R1_001.fastq.gz	RNA-Seq	672.6 MB
Day_7_Control_2_S26_L008_R1_001.fastq.gz	RNA-Seq	424.8 MB
Day_7_Control_2_S27_L008_R1_001.fastq.gz	RNA-Seq	613.2 MB
Day_7_Control_2_S28_L008_R1_001.fastq.gz	RNA-Seq	525.5 MB
Day_7_MALAT1_1_S21_L008_R1_001.fastq.gz	RNA-Seq	539.2 MB
Day_7_MALAT1_1_S22_L008_R1_001.fastq.gz	RNA-Seq	727.0 MB
Day_7_MALAT1_1_S23_L008_R1_001.fastq.gz	RNA-Seq	505.4 MB
Day_7_MALAT1_1_S24_L008_R1_001.fastq.gz	RNA-Seq	484.0 MB
Day_7_MALAT1_2_S29_L008_R1_001.fastq.gz	RNA-Seq	612.0 MB
Day_7_MALAT1_2_S30_L008_R1_001.fastq.gz	RNA-Seq	445.0 MB
Day_7_MALAT1_2_S31_L008_R1_001.fastq.gz	RNA-Seq	793.5 MB
Day_7_MALAT1_2_S32_L008_R1_001.fastq.gz	RNA-Seq	644.1 MB
SRR19217848.lite	RNA-Seq	644.1 MB

GSE203091 GSE via ncbi_elink

GEO

The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression (CUT&RUN)

Mus musculus

13 data files

File	Type	Size
Malat1_MP_1.R1.fastq	OTHER	1.8 GB
Malat1_MP_2.R1.fastq	OTHER	2.0 GB
Malat1_TE_1.R1.fastq	OTHER	1.9 GB
Malat1_TE_2.R1.fastq	OTHER	2.1 GB
Malat1_TE_iso.R1.fastq	OTHER	419.5 MB
NT_Malat1_iso.R1.fastq	OTHER	430.3 MB
NT_MP_1.R1.fastq	OTHER	1.2 GB
NT_MP_2.R1.fastq	OTHER	1.4 GB
NT_MP_iso.R1.fastq	OTHER	706.5 MB
NT_TE_1.R1.fastq	OTHER	1.7 GB
NT_TE_2.R1.fastq	OTHER	1.6 GB
NT_TE_iso.R1.fastq	OTHER	471.4 MB
SRR19221352.lite	OTHER	2.0 GB

GSE203089 GSE via ncbi_elink

GEO

The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression (GRID-Seq)

Mus musculus

12 data files

File	Type	Size
CD8_Day4_1_S5_L001_R1_001.fastq.gz	OTHER	5.1 GB
CD8_Day4_1_S5_L002_R1_001.fastq.gz	OTHER	5.3 GB
CD8_Day4_1_S5_L005_R1_001.fastq.gz	OTHER	2.0 GB
CD8_Day4_1_S5_L006_R1_001.fastq.gz	OTHER	2.0 GB
CD8_Day4_1_S5_L007_R1_001.fastq.gz	OTHER	2.0 GB
CD8_Day4_1_S5_L008_R1_001.fastq.gz	OTHER	2.0 GB
CD8_Day4_2_S6_L001_R1_001.fastq.gz	OTHER	3.4 GB
CD8_Day4_2_S6_L002_R1_001.fastq.gz	OTHER	3.5 GB
CD8_Day4_2_S6_L005_R1_001.fastq.gz	OTHER	2.8 GB
CD8_Day4_2_S6_L006_R1_001.fastq.gz	OTHER	2.8 GB
CD8_Day4_2_S6_L007_R1_001.fastq.gz	OTHER	2.8 GB
CD8_Day4_2_S6_L008_R1_001.fastq.gz	OTHER	2.8 GB

GSE203090 GSE via ncbi_elink

GEO

The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression (ChIP-Seq)

Mus musculus

40 data files

File	Type	Size
MALAT1_A12_Input_S13_L007_R1_001.fastq.gz	ChIP-Seq	610.0 MB
MALAT1_A12_Input_S13_L008_R1_001.fastq.gz	ChIP-Seq	620.6 MB
MALAT1_A12_Input_S21_L005_R1_001.fastq.gz	ChIP-Seq	271.8 MB
MALAT1_A12_Input_S21_L006_R1_001.fastq.gz	ChIP-Seq	269.3 MB
MALAT1_A1_H3K27me3_S1_L005_R1_001.fastq.gz	ChIP-Seq	247.1 MB
MALAT1_A1_H3K27me3_S1_L006_R1_001.fastq.gz	ChIP-Seq	244.2 MB
MALAT1_A1_H3K27me3_S1_L007_R1_001.fastq.gz	ChIP-Seq	1005.6 MB
MALAT1_A1_H3K27me3_S1_L008_R1_001.fastq.gz	ChIP-Seq	1.0 GB
MALAT1_A1_H3K4me3_S11_L005_R1_001.fastq.gz	ChIP-Seq	309.3 MB
MALAT1_A1_H3K4me3_S11_L006_R1_001.fastq.gz	ChIP-Seq	306.0 MB
MALAT1_A1_H3K4me3_S7_L007_R1_001.fastq.gz	ChIP-Seq	155.9 MB
MALAT1_A1_H3K4me3_S7_L008_R1_001.fastq.gz	ChIP-Seq	157.9 MB
MALAT1_A2_H3K27me3_S2_L005_R1_001.fastq.gz	ChIP-Seq	223.7 MB
MALAT1_A2_H3K27me3_S2_L006_R1_001.fastq.gz	ChIP-Seq	222.1 MB
MALAT1_A2_H3K27me3_S2_L007_R1_001.fastq.gz	ChIP-Seq	1.1 GB
MALAT1_A2_H3K27me3_S2_L008_R1_001.fastq.gz	ChIP-Seq	1.1 GB
MALAT1_A2_H3K4me3_S13_L005_R1_001.fastq.gz	ChIP-Seq	332.4 MB
MALAT1_A2_H3K4me3_S13_L006_R1_001.fastq.gz	ChIP-Seq	327.8 MB
MALAT1_A2_H3K4me3_S9_L007_R1_001.fastq.gz	ChIP-Seq	169.1 MB
MALAT1_A2_H3K4me3_S9_L008_R1_001.fastq.gz	ChIP-Seq	172.4 MB
NT_12_Input_S14_L007_R1_001.fastq.gz	ChIP-Seq	448.6 MB
NT_12_Input_S14_L008_R1_001.fastq.gz	ChIP-Seq	455.2 MB
NT_12_Input_S22_L005_R1_001.fastq.gz	ChIP-Seq	323.7 MB
NT_12_Input_S22_L006_R1_001.fastq.gz	ChIP-Seq	324.1 MB
NT_1_H3K27me3_S4_L007_R1_001.fastq.gz	ChIP-Seq	682.4 MB
NT_1_H3K27me3_S4_L008_R1_001.fastq.gz	ChIP-Seq	693.8 MB
NT_1_H3K27me3_S6_L005_R1_001.fastq.gz	ChIP-Seq	134.1 MB
NT_1_H3K27me3_S6_L006_R1_001.fastq.gz	ChIP-Seq	133.5 MB
NT_1_H3K4me3_S10_L007_R1_001.fastq.gz	ChIP-Seq	207.5 MB
NT_1_H3K4me3_S10_L008_R1_001.fastq.gz	ChIP-Seq	209.9 MB
NT_1_H3K4me3_S16_L005_R1_001.fastq.gz	ChIP-Seq	300.7 MB
NT_1_H3K4me3_S16_L006_R1_001.fastq.gz	ChIP-Seq	299.2 MB
NT_2_H3K27me3_S5_L007_R1_001.fastq.gz	ChIP-Seq	933.1 MB
NT_2_H3K27me3_S5_L008_R1_001.fastq.gz	ChIP-Seq	956.1 MB
NT_2_H3K27me3_S7_L005_R1_001.fastq.gz	ChIP-Seq	256.6 MB
NT_2_H3K27me3_S7_L006_R1_001.fastq.gz	ChIP-Seq	254.6 MB
NT_2_H3K4me3_S12_L007_R1_001.fastq.gz	ChIP-Seq	328.3 MB
NT_2_H3K4me3_S12_L008_R1_001.fastq.gz	ChIP-Seq	330.6 MB
NT_2_H3K4me3_S18_L005_R1_001.fastq.gz	ChIP-Seq	300.9 MB
NT_2_H3K4me3_S18_L006_R1_001.fastq.gz	ChIP-Seq	300.4 MB

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The long noncoding RNA Malat1 regulates CD8+ T cell differentiation by mediating epigenetic repression