science.sciencemag.org/content/371/6524/eabb6896/suppl/DC1

Supplementary Materials for QRICH1 dictates the outcome of ER stress through transcriptional

control of proteostasis

Kwontae You, Lingfei Wang, Chih-Hung Chou, Kai Liu, Toru Nakata, Alok Jaiswal, Junmei Yao, Ariel Lefkovith, Abdifatah Omar, Jacqueline G. Perrigoue, Jennifer E. Towne,

Aviv Regev‡, Daniel B. Graham‡, Ramnik J. Xavier‡

‡Corresponding author. Email: dgraham@broadinstitute.org (D.B.G.); aregev@broadinstitute.org (A.R.); xavier@molbio.mgh.harvard.edu (R.J.X.)

Published 1 January 2021, Science 371, eabb6896 (2021) DOI: 10.1126/science.abb6896

This PDF file includes:

Figs. S1 to S7 Captions for Tables S1 to S4 References

Other Supporting Online Material for this manuscript includes the following: (available at science.sciencemag.org/content/371/6524/eabb6896/suppl/DC1)

MDAR Reproducibility Checklist (.pdf) Tables S1 to S4 (.xlsx)

CBEnterocyte

Villin

Goblet cells Tuft cells

Alcian Blue(MUC) Dclk1

Rel

ativ

e ce

llab

unda

nce

100

DMSO Tm-13h Tm-25h

EnterocytesGoblet Cells

10-1

●●

●

●

●

●

●

●

●

●regulation of oxidative phosphorylation

negative regulation of macroautophagy

mRNA catabolic process

translational initiation

tRNA aminoacylation for protein translation

protein localization to endoplasmic reticulum

ER to Golgi vesicle−mediated transport

response to endoplasmic reticulum stress

mRNA metabolic process

peptide biosynthetic process

1.5 2.0 2.5 3.0 3.5−log10P.adj

1.5

2.0

2.5

3.0

−log10P.adj

No. of genes●

●

●●

5101520

GO enrichmentE

D

L−amino acid transporttranslational initiation

positive regulation of transcription from RNA pol II promoter in response to ER stressER−nucleus signaling pathway

signal peptide processingL−serine biosynthetic process

protein foldingcell redox homeostasis

protein localization to ERintrinsic apoptotic signaling pathway in response to ER stress

ER to Golgi vesicle−mediated transportprotein N−linked glycosylation

peptide biosynthetic processcellular amino acid metabolic process

response to ER stress

All

Goble

t

Enter

ocyte

10

20

30

No. of Genes10203040

GO enrichment

−log10P.adj

A

EnterocytesGoblet CellsTuft Cells

Cluster-louvain-1-10

logtmeanmitochondrial DNA

Conditions

Cell types

Tm-13h-1Tm-13h-2Tm-25h-1Tm-25h-2

DMSO-1DMSO-2

01101112131423456789

2

Fig. S1. scRNA-seq of intestinal monolayer cells shows the terminal-UPR signature during ER stress.

(A) tSNE plots show the clustering of monolayer cells (colored by conditions, clusters, and celltypes).

(B) Immunostaining of monolayer cells. Enterocytes, goblet cells, and Tuft cells are detected byVillin, Alcian Blue (Mucin), and Dclk1 staining.

(C) Changes in relative abundance of enterocytes and goblet cells after Tm treatment. Twosamples were measured per conditions, with + signs indicating percentage of cells for eachmeasurement.

(D) Gene set enrichment analysis (GSEA) shows enriched pathways in goblet cells andenterocytes upon 13 h of Tm treatment.

(E) GSEA shows the enriched biological processes in the terminal-UPR signature illustrated inFig. 1H.

3

4

Fig. S2. XBP1s-GFP reporter screens identify potent regulators of the ER stress-UPR pathway.

(A) Dose-dependent response to Tunicamycin (Tm). Quantification of spliced XBP1 (XBP1s)level according to GFP intensity using FACS after 14 h of Tm treatment.

(B) Gating strategy. The lowest and highest 15% of cells were sorted out based on the GFPintensities using FACS sorter.

(C) Volcano plot shows the average gRNA enrichments in the non-stressed XBP1s screen. Thedashed line indicates the p-value cut-off. Known UPR genes and terminal-UPR genes arehighlighted in red and blue, respectively.

(D) GSEA shows the enriched biological processes in the non-stressed XBP1s screen. Only thelist of genes for which KO promotes UPR activity is used for the GO analysis. Many of the knownER homeostasis-related GOs are shown on this screen.

(E) GSEA shows enriched biological processes in the stressed XBP1s screen. UP and DN indicatethe list of genes for which KO promotes or reduces XBP1s expression in the Tm-treated cells.

(F) Volcano plot of ER stress XBP1s screen shows the distribution of essential genes, highlightedin red.

(G) Measurement of GFP intensities shows the level of XBP1s in wild-type (dashed black) or KO(filled blue) cells treated with DMSO. The symbol indicates the targeted gene. The dashed red lineindicates the GFP intensity in the Tm condition.

5

6

Fig. S3. QRICH1 regulates cell viability during ER stress.

(A) Schematic diagram of the domain structure of QRICH1. Figure modified from theRCSB_PDB: Q2TAL8 (http://www.rcsb.org/pdb/protein/Q2TAL8).

(B) The proportion of 7-AAD and/or Annexin V positive cells. sgNCtrl or sgQRICH1 transducedcells treated with Tm for the indicated time (n=2).

(C) Left panel: Measurement of DDIT3 or HSPA5 in HT29 cells after the transduction ofCRISPRa amplifiers by qRT-PCR. Right panel: Transcriptional induction of QRICH1 byCRISPRa. Mean value of three guides. Error bars, mean +/- SD.

(D) Immunoblot shows expression patterns of QRICH1 upon Tm treatment in the sgNCtrl or sgPERK transduced HT29 cells. A representative blot is shown (n=3, two-way ANOVA).

(E) Quantification of QRICH1 mRNA (n=4) and protein level (n=3) in cells treated with0.3ug/ml of Tm for 1 day (multiple t-test).

(F) Schematic diagram of upstream open reading frame (uORF) mediated translational controldepends on the status of eIF2α phosphorylation.

(G) Schematic diagram shows QRICH1 mRNA isoforms. All variants encode the same protein— variant 4 was used for QRICH1 reconstitution.

For panels D and E: *p

8

Fig. S4. QRICH1 facilitates protein secretion during ER stress.

(A) Immunoblot shows the kinetics of p-eIF2α, QRICH1, ATF4, and QRICH1-regulated targetgenes during prolonged ER stress. A representative blot is shown.

(B) FACS analysis shows the level of XBP1s in DMSO-treated wild-type (black line) or sgRNAtransduced (filled blue) cells, as measured by GFP intensities. The target gene is indicated above each plot.

(C) Assessment of protein synthesis rate in the cytosolic or ER/membrane fractions detected usinganti-puromycin. WT and QRICH1 KO cells were pulse-labeled with puromycin after Tm treatment for 3 days. The DMSO-sgNCtrl in cytosol and ER/memb were set to 100%, and were used to normalize the data in the cytosol and ER/memb fractions, respectively (n=2). ACTB and PERK were used as markers for cytosol and ER fractions, respectively.

9

10

Fig. S5. QRICH1 regulation during ER stress mediates proteotoxicity in primary mouse intestinal epithelium.

(A) Immunoblot analysis of WT and Qrich1 knockout (sgQrich1) mouse intestinal monolayers.Three different Cas9 guides are noted A, B, and C.

(B and C) WT or Qrich1 KO mouse intestinal monolayer cells were exposed to an indicated dose of Tm for 24 h. Quantification of cleaved Caspase 3 in those cells are measured by ImageJ (n=3, two-way ANOVA).

(D) The activity of Caspase 3 was measured by in vitro Caspase 3 assay with fluorogenicCaspase 3 substrate (Z-DEVD-AMC) in WT or Qrich1 KO monolayer cells treated with Tm for24 h (n=3, two-way ANOVA). RFU, relative fluorescence unit.

(E) Caspase 3 activity in the GFP or human QRICH1 transduced mouse intestinal organoidstreated with DMSO or Tm for 24 h (n=3, two-way ANOVA).

For panels C-E: *p

12

Fig. S6. Experimental scheme to measuring cell type-specific protein synthesis rate in human intestinal organoids during ER stress.

(A) Expression patterns of MUC2 and TMIGD1 in the mouse and human intestinal epithelium.(17, 33). TPM denotes transcripts per million, TP10K denotes UMI counts normalized by thetotal number of UMIs per cell and converted to transcripts-per-10,000.

(B) Schematic of the workflow for hISC experiments and FACS analysis.

13

14

Fig. S7. Expression of QRICH1 signature in inflamed conditions.

(A) Module score of the QRICH1_signature mapped to epithelial cells from the colon of healthyindividuals and the inflamed colon of UC patients. Cell types are annotated according topreviously annotated marker genes (69).

(B) Heatmap shows the scaled average expression levels of each gene in the QRICH1_signatureacross the epithelial cell types in the colon of healthy individuals and patients with ulcerativecolitis (inflamed regions).

15

Table S1. (separate Excel file) Differentially expressed genes for cell subsets and the terminal-UPR geneset from the ER stressed monolayer shown in Fig. 1H.

Table S2. (separate Excel file) CRISPR-Cas9 Genome-wide screen data for ER stress-UPR pathway using the XBP1s-GFP reporter cells in Fig. 2.

Table S3. (separate Excel file) ChIP-seq data using anti-QRICH1 and ATF4 and Gene Ontology results illustrated in Fig. 4.

Table S4. (separate Excel file) Differentially expressed genes between WT and QRICH1 KO cells in response to Tm treatment are listed. Related to Fig. 5A.

16

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202010_Science_QRICH1_SupplementaryMaterials.pdfabb6896_You_SM.refs.pdfReferences and Notes