Samy Coulombe’s research while affiliated with McGill University and other places

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Publications (4)


Laplacian Change Point Detection for Single and Multi-view Dynamic Graphs
  • Article

November 2023

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15 Reads

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6 Citations

ACM Transactions on Knowledge Discovery from Data

Shenyang Huang

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Samy Coulombe

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[...]

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Dynamic graphs are rich data structures that are used to model complex relationships between entities over time. In particular, anomaly detection in temporal graphs is crucial for many real world applications such as intrusion identification in network systems, detection of ecosystem disturbances and detection of epidemic outbreaks. In this paper, we focus on change point detection in dynamic graphs and address three main challenges associated with this problem: i) how to compare graph snapshots across time, ii) how to capture temporal dependencies, and iii) how to combine different views of a temporal graph. To solve the above challenges, we first propose Laplacian Anomaly Detection (LAD) which uses the spectrum of graph Laplacian as the low dimensional embedding of the graph structure at each snapshot. LAD explicitly models short term and long term dependencies by applying two sliding windows. Next, we propose MultiLAD, a simple and effective generalization of LAD to multi-view graphs. MultiLAD provides the first change point detection method for multi-view dynamic graphs. It aggregates the singular values of the normalized graph Laplacian from different views through the scalar power mean operation. Through extensive synthetic experiments, we show that i) LAD and MultiLAD are accurate and outperforms state-of-the-art baselines and their multi-view extensions by a large margin, ii) MultiLAD’s advantage over contenders significantly increases when additional views are available, and iii) MultiLAD is highly robust to noise from individual views. In five real world dynamic graphs, we demonstrate that LAD and MultiLAD identify significant events as top anomalies such as the implementation of government COVID-19 interventions which impacted the population mobility in multi-view traffic networks.


Schematic of the human (A) and mouse (B) HOXA gene clusters. Left-facing arrows represent HOXA genes and lncRNA genes are below each cluster. The shared HOXA and HOTAIRM1 promoter region is expanded below the clusters.
Depleting HOTAIRM1 hampers cell proliferation during neuronal differentiation. (A) schematic of the method used to differentiate cells. (B) Outline of the live cell imaging procedure used to track cell confluency. (C) NT2-D1 confluency changes in the absence (−RA) or presence (+RA) of retinoic acid as captured by live cell imaging. Timepoints reflect when pictures were taken as indicated in (B). (D) Representative phase contrast microscopy images of -RA or +RA NT2-D1 cells at the start (day 0) and end (day 3) of the differentiation time-course monitored in (C). (E) Steady-state levels of HOTAIRM1 lncRNA variants of collected samples monitored in (C). (F) Diagram indicating HOTAIRM1 regions targeted by siRNAs or quantified by RT-qPCR. 5’ to 3’ directionality is indicated by 7-methylguanosine cap (m7G) and poly(A) tail (pA); ‘E’ and ‘I’ represent exons and introns, respectively. (G) Outline of the live cell imaging procedure (top) used to track cell confluency (bottom). (H) Steady-state levels of HOTAIRM1 variants and HOXA1 in RNAi knockdown samples monitored in (I) and collected after 3 days of RA treatment. HOXA1 expression values were divided by 10 to display on the same scale as HOTAIRM1. (I) Confluency changes of NT2-D1 cells transfected with siRNAs targeting HOTAIRM1 or a negative control. Timepoints reflect when pictures were taken post RA treatment as indicated in (G). Yellow shading highlights exponential growth delay when HOTAIRM1 is depleted. Error bars in cell confluency graphs (C, I) show the standard error of the mean (sem) across 12 culture dish regions, whereas error bars in expression level graphs (E, H) are the standard deviations (stdevs) between at least 3 RT-qPCR measurements. Numbers above histogram bars are fold differences relative to corresponding siNC levels.
HOTAIRM1 is required for proper neuronal differentiation. (A) SOX3 and HOTAIRM1 expression during a differentiation time-course in NT2-D1. Error bars are stdevs from three biological replicates, each with at least three measurements. *SOX3 values are relative to PGK1 whereas those for HOTAIRM1 are relative to actin (10⁻⁴). (B,C) SOX3 (B) or HOTAIRM1 and HOXA1 (C) expression in RNAi knockdown samples of NT2-D1 treated 3 days with RA. Expression values are from at least three measurements each from three independent biological replicates. Error bars represent the (sem). Numbers above histogram bars indicate fold differences relative to corresponding siNC samples. (D) SOX3 and HOTAIRM1 expression during an NCCIT differentiation time-course. Expression levels were measured as in (A). A biological replicate extending to Day 14 post-RA is in Supplemental Figure S2A. (E,F) SOX3 (E) or HOTAIRM1 and HOXA1 (F) expression in NCCIT RNAi knockdown samples treated 3 days with RA. Expression values are averages from at least three measurements and error bars are stdevs. Numbers above histogram bars are fold differences relative to corresponding siNC samples. A replicate of (E,F) collected 5 days post-RA is in Supplemental Figure S2B,C. A third biological replicate of Day 3 post-RA is given in Supplemental Figure S3E,F. Note that HOXA1 values in (C,F) were divided by 10 to be on a scale comparable to HOTAIRM1. (G) Expression of HOTAIRM1 and differentiation markers before and after RA induction for 3 days in NT2-D1. Error bars are stdevs from at least three measurements. HOTAIRM1 values were divided by 100 for direct comparison with other genes. (H) Expression in RNAi knockdown samples of NT2-D1 treated 3 days with RA. Expression values are from at least three measurements and error bars represent the stdev. HOTAIRM1 values were divided by 100 for direct comparison with other genes. Numbers above histogram bars indicate fold differences relative to corresponding siNC samples. RNA levels were quantified by RT-qPCR using primers listed in Supplemental Table S1. (I) Western blot analysis of SOX3 and HES1 protein levels in control (siNC) and HOTAIRM1-depleted (siM1.0, siM1.3) NCCIT cells treated with RA for 3 days.
HOTAIRM1 associates with the HOXA1 transcription factor in different cell types and species. (A) Diagram of the highly conserved, shared promoter region from which HOXA1 and HOTAIRM1 are transcribed on opposite strands. Base-wise conservation across 100 vertebrates by phyloP and base change locations between human and mouse is shown below. (B) HOXA1 and HOTAIRM1 RA induction kinetics in two neuronal differentiation models. RNA levels measured during RA (10 µM) induction time-courses in NT2-D1 (left) or NCCIT (right) using RT-qPCR. (C) Outline of the RNA immunoprecipitation (RIP) procedure. Note that RA is added 6 hours post-transfection, and that cells are collected either 2 or 3 days after RA treatment as specified in each panel. (D) Transfected Flag-hHOXA1 is specifically immunoprecipitated in RA-induced NCCIT cells. Western blot analysis of the input (1%) and RIP (5%) samples from one of the biological replicates analysed in (E), with eukaryotic translation elongation factor 2 (eEF2) probed as a control for specificity. (E) HOXA1 preferentially binds spliced HOTAIRM1 in RA-induced NCCIT cells. RIPs are from three biological replicates quantified by RT-qPCR. (F) Induction of mouse Hoxa1 and Hotairm1 by RA (1 µM) in P19 cells. (G) Transfected Flag-mHoxa1 is specifically immunoprecipitated in RA-induced P19 cells. Western blot analysis of the input (1%) and RIP (5%) samples corresponding to the assay shown in (H). (H) Mouse Hoxa1 preferentially binds mHotairm1 in RA-induced P19 cells. RT-qPCR measurements are from at least three PCRs with errors bars representing stdevs.
Depleting HOXA1 during differentiation delays NANOG downregulation. (A) NANOG and HOXA1 engage in positive auto- and negative cross-regulatory feedback mechanisms to control their gene expression. HOTAIRM1 (dashed) is proposed to work with HOXA1 as an RNP on the NANOG and HOXA1/HOTAIRM1 loci in both undifferentiated and RA-induced cell states; RARE = Retinoic Acid Response Element, ARE = Autonomous Response Element, NBS = NANOG Binding Site, HBS = HOXA1 Binding Site. (B) Steady-state NANOG and HOXA1 mRNA levels throughout RA-induced differentiation of NT2-D1 (left) or NCCIT (right) cells. *Relative HOXA1 mRNA levels were divided by 10 to display on the same scale with NANOG. (C,D) HOXA1 knockdown delays NANOG downregulation, blunts SOX3 upregulation, and impedes HOTAIRM1 induction during NT2-D1 differentiation. HOXA1 was RNAi-depleted and cells were collected 3 days after RA treatment (C) or every 24 hours along a time-course (D). A similar differentiation time-course for control (siNC) and HOXA1 (siA1) knockdown cells in NCCIT is shown in (E). RNA levels were measured by RT-qPCR from at least three measurements, with error bars showing stdevs. Numbers above histogram bars are fold differences relative to levels in siNC samples.

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A conserved HOTAIRM1-HOXA1 regulatory axis contributes early to neuronal differentiation
  • Article
  • Full-text available

September 2023

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45 Reads

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1 Citation

HOTAIRM1 is unlike most long non-coding RNAs in that its sequence is highly conserved across mammals. Such evolutionary conservation points to it having a role in key cellular processes. We previously reported that HOTAIRM1 is required to curb premature activation of downstream HOXA genes in a cell model recapitulating their sequential induction during development. We found that it regulates 3’ HOXA gene expression by a mechanism involving epigenetic and three-dimensional chromatin changes. Here we show that HOTAIRM1 participates in proper progression through the early stages of neuronal differentiation. We found that it can associate with the HOXA1 transcription factor and contributes to its downstream transcriptional program. Particularly, HOTAIRM1 affects the NANOG/POU5F1/SOX2 core pluripotency network maintaining an undifferentiated cell state. HOXA1 depletion similarly perturbed expression of these pluripotent factors, suggesting that HOTAIRM1 is a modulator of this transcription factor pathway. Also, given that binding of HOTAIRM1 to HOXA1 was observed in different cell types and species, our results point to this ribonucleoprotein complex as an integral part of a conserved HOTAIRM1-HOXA1 regulatory axis modulating the transition from a pluripotent to a differentiated neuronal state.

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Laplacian Change Point Detection for Single and Multi-view Dynamic Graphs

February 2023

·

10 Reads

Dynamic graphs are rich data structures that are used to model complex relationships between entities over time. In particular, anomaly detection in temporal graphs is crucial for many real world applications such as intrusion identification in network systems, detection of ecosystem disturbances and detection of epidemic outbreaks. In this paper, we focus on change point detection in dynamic graphs and address three main challenges associated with this problem: i). how to compare graph snapshots across time, ii). how to capture temporal dependencies, and iii). how to combine different views of a temporal graph. To solve the above challenges, we first propose Laplacian Anomaly Detection (LAD) which uses the spectrum of graph Laplacian as the low dimensional embedding of the graph structure at each snapshot. LAD explicitly models short term and long term dependencies by applying two sliding windows. Next, we propose MultiLAD, a simple and effective generalization of LAD to multi-view graphs. MultiLAD provides the first change point detection method for multi-view dynamic graphs. It aggregates the singular values of the normalized graph Laplacian from different views through the scalar power mean operation. Through extensive synthetic experiments, we show that i). LAD and MultiLAD are accurate and outperforms state-of-the-art baselines and their multi-view extensions by a large margin, ii). MultiLAD's advantage over contenders significantly increases when additional views are available, and iii). MultiLAD is highly robust to noise from individual views. In five real world dynamic graphs, we demonstrate that LAD and MultiLAD identify significant events as top anomalies such as the implementation of government COVID-19 interventions which impacted the population mobility in multi-view traffic networks.


Figure 2. Depleting HOTAIRM1 hampers cell proliferation during neuronal differentiation.
Figure 4. HOTAIRM1 associates with the HOXA1 transcription factor in different cell types
Figure 6. Depleting HOTAIRM1 during neuronal differentiation delays NANOG
Figures and Legends
A conserved HOTAIRM1-HOXA1 regulatory axis coordinates early neuronal differentiation

August 2022

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80 Reads

HOTAIRM1 is unlike most long non-coding RNAs in that its sequence is highly conserved across mammals. Such evolutionary conservation points to it having a role in key cellular processes. We previously reported that HOTAIRM1 is required to curb premature activation of downstream HOXA genes in a cell model recapitulating their sequential induction during development. We found that it regulates 3' HOXA gene expression by a mechanism involving epigenetic and three-dimensional chromatin changes. Here we show that HOTAIRM1 is required for proper progression through the early stages of neuronal differentiation. We found that it associates with the HOXA1 transcription factor and participates in its downstream transcriptional program. Particularly, HOTAIRM1 affects the NANOG/POU5F1/SOX2 core pluripotency network maintaining an undifferentiated cell state. HOXA1 depletion similarly perturbed expression of these pluripotent factors, suggesting that HOTAIRM1 is a modulator of this transcription factor pathway. Also, given that binding of HOTAIRM1 to HOXA1 was observed in different cell types and species, our results point to this ribonucleoprotein complex as an integral part of a conserved HOTAIRM1-HOXA1 regulatory axis controlling the transition from a pluripotent to a differentiated neuronal state.

Citations (2)


... Tollis et al. used a model system that recapitulates spinal MN (spMN) differentiation to show nHOTAIRM1 intervened in the binary cell fate decision between MNs and interneurons, acting as a pro-MN factor [80]. A recent study indicated that HOTAIRM1 participated in proper progression through the early stages of neuronal differentiation, HOTAIRM1 affected the NANOG/POU5F1/SOX2 core pluripotency network maintaining an undifferentiated cell state [81]. Wang et al. identified that HOTAIRM1 as a novel regulator of osteogenic differentiation of BMSCs by the regulation of miR-152-3p/ETS1 axis, uncovering HOTAIRM1 as a promising therapeutic strategy for osteoporosis [68]. ...

Reference:

Role of the lncRNA HOX antisense intergenic RNA myeloid 1 in Cancer: A Review
A conserved HOTAIRM1-HOXA1 regulatory axis contributes early to neuronal differentiation

... To detect whether or not a power system has anomalies, we compare the global connectivity (i.e., the overall similarity of bus voltages) of the spatiotemporal graphs at different times. The global connectivity of a spatial graph can be quantified by the Fiedler value (i.e., the second smallest eigenvalue λ 2 ) of the generalized graph Laplacian matrix [16][17][18]. A larger λ 2 indicates that the entire graph has strong connectivity as all nodes are well-connected. ...

Laplacian Change Point Detection for Single and Multi-view Dynamic Graphs
  • Citing Article
  • November 2023

ACM Transactions on Knowledge Discovery from Data