In situ sequence-specific visualization of single methylated cytosine on tissue sections using ICON probe and rolling-circle amplification

Histochemistry and cell biology

2022 Nov 23

Kitazawa, S;Haraguchi, R;Takaoka, Y;Kitazawa, R;
PMID: 36418613 | DOI: 10.1007/s00418-022-02165-2

Since epigenetic modifications differ from cell to cell, detecting the DNA methylation status of individual cells is requisite. Therefore, it is important to conduct "morphology-based epigenetics research", in which the sequence-specific DNA methylation status is observed while maintaining tissue architecture. Here we demonstrate a novel histochemical technique that efficiently shows the presence of a single methylated cytosine in a sequence-dependent manner by applying ICON (interstrand complexation with osmium for nucleic acids) probes. By optimizing the concentration and duration of potassium osmate treatment, ICON probes selectively hybridize to methylated cytosine on tissue sections. Since the elongation process by rolling-circle amplification through the padlock probe and synchronous amplification by the hyperbranching reaction at a constant temperature efficiently amplifies the reaction, it is possible to specifically detect the presence of a single methylated cytosine. Since the ICON probe is cross-linked to the nuclear or mitochondrial DNA of the target cell, subsequent elongation and multiplication reactions proceed like a tree growing in soil with its roots firmly planted, thus facilitating the demonstration of methylated cytosine in situ. Using this novel ICON-mediated histochemical method, detection of the methylation of DNA in the regulatory region of the RANK gene in cultured cells and of mitochondrial DNA in paraffin sections of mouse cerebellar tissue was achievable. This combined ICON and rolling-circle amplification method is the first that shows evidence of the presence of a single methylated cytosine in a sequence-specific manner in paraffin sections, and is foreseen as applicable to a wide range of epigenetic studies.

VP.59 A single-arm, open-label, multicenter study of tranilast for advanced heart failure in patients with muscular dystrophy

Neuromuscular Disorders

2022 Oct 01

Matsumura, T;Hashimoto, H;Sekimizu, M;Saito, A;Asakura, M;Kimura, K;Iwata, Y;
| DOI: 10.1016/j.nmd.2022.07.253

The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. Myocytes' damage induces TRPV2 expression on the sarcolemma, which causes calcium influx into the cytoplasm, and triggers degeneration. TRPV2 inhibition was effective in animal models of cardiomyopathy and muscular dystrophy (MD). Our pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Then, we planned a study to evaluate the safety and efficacy of tranilast for heart failure of MD patients. Subjects were MD patients whose serum BNP levels exceeded 100 pg/mL despite receiving standard therapy. Tranilast was administered orally at 100 mg thrice daily. The primary endpoint was the change in log (BNP) (⊿log [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous carvedilol study that resulted in a mean population ⊿log [BNP] of 0.18. TRPV2 expression on the mononuclear cell (MNC) surface, cardiac events, left ventricular fractional shortening (FS), human atrial natriuretic peptide (hANP), creatine kinase, and pinch strength were also assessed. Because of the poor general condition of many patients, among 18 patients included, 13 patients could be treated according to the protocol throughout the 6-month period. There were no serious adverse events related to tranilast except diarrhea, a known adverse effect. TRPV2 expression on the MNC surface was elevated at baseline and reduced after treatment. BNP, hANP, and FS remained stable. In the per-protocol set group, ⊿log [BNP] was -0.2 and significantly lower than that in the null hypothesis. In conclusion, tranilast is safe and effectively inhibits TRPV2 expression, even in MD patients with advanced heart failure. To evaluate the efficacy of tranilast in preventing heart failure, motor impairment, and respiratory failure, we are planning a study for mild MD patients.

A02 Altered epigenetic and transcriptional regulation during striatum-dependent memory in HD mice

A: Pathogenic mechanisms

2022 Sep 01

Alcalá-Vida, R;Lotz, C;Seguin, J;Decraene, C;Brulé, B;Awada, A;Bombardier, A;Cosquer, B;Pereira de Vasconcelos, A;Brouillet, E;Cassel, J;Boutillier, A;Merienne, K;
| DOI: 10.1136/jnnp-2022-ehdn.2

Epigenetic mechanisms are altered in the striatum of HD patients and mouse models, but how they might contribute to pathogenesis, including cognitive deficits, is unclear. Epigenetic regulation is critical to learning and memory processes, through transcriptional control of gene program promoting neural plasticity. We asked whether memory-associated epigenetic and transcriptional responses were impaired in HD R6/1 mice. To this end, we trained R6/1 mice (and control mice) in an aquatic navigation task, the double H maze, which allows assessing striatum-dependent memory (e.g. egocentric spatial memory). We then generated ChIP-seq, 4C-seq and RNA-seq datasets on striatal tissue of HD and control mice during egocentric memory processing, including memory acquisition and consolidation/recall. Egocentric memory was altered since early symptomatic stage in R6/1 mice, which correlated with dramatic reduction of striatal epigenetic and transcriptional changes induced by memory process. More specifically, multi-omic analysis showed that, during memory acquisition, 3D chromatin re-organization and transcriptional induction at BDNF-related genes were diminished in R6/1 striatum. Moreover, we found that changes in H3K9 acetylation (H3K9ac), which accompanied memory process in normal striatum, were attenuated in R6/1 striatum. Functional enrichment analyses further indicated that altered H3K9ac regulation during late phase of egocentric memory process (e.g. consolidation/recall) contributed to impaired TGFβ-dependent cellular plasticity. Together, this study provides support to the hypothesis that epigenetic dysregulation in HD contributes to cognitive deficits, and shed light on new targets of striatal plasticity, particularly H3K9ac and TFGβ signaling.

A01 Somatic mosaicism of the HTT cag repeat in intermediate allele carriers with neurocognitive symptoms compatible with huntington disease

A: Pathogenic mechanisms

2022 Sep 01

Ruiz de Sabando, A;Ciosi, M;Galbete, A;Monckton, D;Ramos-Arroyo, M;
| DOI: 10.1136/jnnp-2022-ehdn.1

We aimed to determine the possible role of CAG somatic expansions on the clinical expression of intermediate allele (IA) carriers of the HTT gene, responsible for Huntington disease (HD). We performed exon one sequencing analysis of the HTT gene on peripheral blood DNA in a Spanish cohort of asymptomatic IA carriers (n=55), symptomatic IA carriers (n=86) and HD subjects (n=124). Additionally, we investigated different brain regions of an individual carrying an HTT allele with 33 CAGs, with neurocognitive symptoms. Linear regression models were used to analyse the association between CAG length and age with somatic mosaicism. Symptomatic IA carriers presented with motor (80%), cognitive (20%) and/or behavioural (22%) signs, and an average age of onset of 58.7 years±18.6. Somatic mosaicism is CAG- and age-dependent in alleles of CAG≥27 CAGs, with b=0.04 (95% CI: 0.035-0.046), and b=0.001 (95% CI: 0.001-0.002), respectively, for all IAs. There was no statistical difference between HTT somatic mosaicism in symptomatic vs asymptomatic IA carriers (p=0.066). Somatic expansions of +1 and +2 CAGs were detected in the brain of the individual with 33 CAGs, with the highest expansion ratio observed in the putamen, where up to 10% of the DNA molecules underwent somatic expansion. In conclusion, somatic CAG expansions observed in blood cannot explain, overall, the neurocognitive signs of IA carriers. However, somatic instability occurs in IAs, which changes with CAG number and age; therefore, the presence of cells in the brain that express up to +2 CAGs may be important when considering the phenotypes of those alleles close to the pathological threshold.

Loss of KLK4::KLKP1 pseudogene expression by RNA chromogenic in-situ hybridization is associated with PTEN loss and increased risk of biochemical recurrence in a cohort of middle eastern men with prostate cancer

Journal of cancer research and clinical oncology

2022 Aug 18

Bakker, A;Slack, JC;Palanisamy, N;Carskadon, S;Ghosh, S;Khalifeh, I;Bismar, TA;
PMID: 35982181 | DOI: 10.1007/s00432-022-04279-5

KLK4::KLKP1 fusion is a recently described pseudogene that is enriched in prostate cancer (PCa). This new biomarker has not been characterized in the Middle Eastern population.To establish the incidence and prognostic value of KLK4::KLKP1 fusion in a cohort of Middle Eastern men with PCa and explore the relationship of this marker to other relevant biomarkers (PTEN, ERG, SPINK1).We interrogated a cohort of 340 Middle Eastern men with localized PCa treated by radical prostatectomy between 2005 and 2015. KLK4::KLKP1 fusion status was assessed by RNA Chromogenic in situ hybridization (CISH) and correlated to pathological and clinical parameters.RNA-CISH expression of KLK4::KLKP1 was correlated with prognostic factors, ERG, PTEN, and SPINK1 expression, and biochemical recurrence (BCR) following prostatectomy.51.7% of patient samples showed positive KLK4::KLKP1 expression; more commonly in cores of PCa (38%) versus non-cancer (20.6%) (p < 0.0001) and in lower Gleason Grade Group tumors (1-3) vs (4-5). KLK4::KLKP1 expression positively correlated with ERG positivity and inversely associated with PTEN loss. No significant association was found with SPINK1 expression, seminal vesicle invasion, positive surgical margin, pathological stage, or patient age (< 50 or ≥ 50). The association between PTEN loss and BCR increased when combined with KLK4::KLKP1 negativity (HR 2.31, CI 1.03-5.20, p = 0.042).KLK4::KLKP1 expression is more common in this cohort of Middle Eastern men than has been reported in North American men. It is associated with ERG positivity and inversely correlated with PTEN loss. In isolation, KLK4::KLKP1 expression was not significantly associated with clinical outcome or pathological parameters. However, its expression is associated with certain molecular subtypes (ERG-positive, PTEN-intact) and as we demonstrate may help further stratify the risk of recurrence within these groups.

Colocalization of Gene Expression and DNA Methylation with Genetic Risk Variants Supports Functional Roles of MUC5B and DSP in Idiopathic Pulmonary Fibrosis

American journal of respiratory and critical care medicine

2022 Jul 11

Borie, R;Cardwell, J;Konigsberg, IR;Moore, CM;Zhang, W;Sasse, SK;Gally, F;Dobrinskikh, E;Walts, A;Powers, J;Brancato, J;Rojas, M;Wolters, PJ;Brown, KK;Blackwell, TS;Nakanishi, T;Richards, JB;Gerber, AN;Fingerlin, TE;Sachs, N;Pulit, SL;Zappala, Z;Schwartz, DA;Yang, IV;
PMID: 35816432 | DOI: 10.1164/rccm.202110-2308OC

Common genetic variants have been associated with idiopathic pulmonary fibrosis (IPF).To determine functional relevance of the 10 IPF-associated common genetic variants we previously identified.We performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals and functional validation by luciferase reporter assays. Illumina MEGA genotyping arrays, mRNA sequencing, and Illumina 850k methylation arrays were performed on lung tissue of participants with IPF (234 RNA and 345 DNA samples) and non-diseased controls (188 RNA and 202 DNA samples).Focusing on genetic variants within 10 IPF-associated genetic loci, we identified 27 eQTLs in controls and 24 eQTLs in cases (false-discovery-rate-adjusted p<0.05). Among these signals, we identified associations of lead variants rs35705950 with expression of MUC5B and rs2076295 with expression of DSP in both cases and controls. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. We also demonstrated strong co-localization of eQTL/mQTL and genetic signal in MUC5B (rs35705950) and DSP (rs2076295). Functional validation of the mQTL in MUC5B using luciferase reporter assays demonstrates that the CpG resides within a putative internal repressor element.We have established a relationship of the common IPF genetic risk variants rs35705950 and rs2076295 with respective changes in MUC5B and DSP expression and methylation. These results provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.

Simultaneous Multiplexed Imaging of Biomolecules in Transgenic Mouse Brain Tissues Using Mass Spectrometry Imaging: A Multi-omic Approach

Analytical chemistry

2022 Jun 13

Le, MT;Shon, HK;Nguyen, HP;Lee, CH;Kim, KS;Na, HK;Lee, TG;
PMID: 35696262 | DOI: 10.1021/acs.analchem.2c00676

The importance of multi-omic-based approaches to better understand diverse pathological mechanisms including neurodegenerative diseases has emerged. Spatial information can be of great help in understanding how biomolecules interact pathologically and in elucidating target biomarkers for developing therapeutics. While various analytical methods have been attempted for imaging-based biomolecule analysis, a multi-omic approach to imaging remains challenging due to the different characteristics of biomolecules. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a powerful tool due to its sensitivity, chemical specificity, and high spatial resolution in visualizing chemical information in cells and tissues. In this paper, we suggest a new strategy to simultaneously obtain the spatial information of various kinds of biomolecules that includes both labeled and label-free approaches using ToF-SIMS. The enzyme-assisted labeling strategy for the targets of interest enables the sensitive and specific imaging of large molecules such as peptides, proteins, and mRNA, a task that has been, to date, difficult for any MS analysis. Together with the strength of the analytical performance of ToF-SIMS in the label-free tissue imaging of small biomolecules, the proposed strategy allows one to simultaneously obtain integrated information of spatial distribution of metabolites, lipids, peptides, proteins, and mRNA at a high resolution in a single measurement. As part of the suggested strategy, we present a sample preparation method suitable for MS imaging. Because a comprehensive method to examine the spatial distribution of multiple biomolecules in tissues has remained elusive, our strategy can be a useful tool to support the understanding of the interactions of biomolecules in tissues as well as pathological mechanisms.

Autism-associated mutations in KV7 channels induce gating pore current

Proceedings of the National Academy of Sciences of the United States of America

2021 Nov 09

Gamal El-Din, TM;Lantin, T;Tschumi, CW;Juarez, B;Quinlan, M;Hayano, JH;Li, J;Zweifel, LS;Catterall, WA;
PMID: 34728568 | DOI: 10.1073/pnas.2112666118

Autism spectrum disorder (ASD) adversely impacts >1% of children in the United States, causing social interaction deficits, repetitive behaviors, and communication disorders. Genetic analysis of ASD has advanced dramatically through genome sequencing, which has identified >500 genes with mutations in ASD. Mutations that alter arginine gating charges in the voltage sensor of the voltage-gated potassium (KV) channel KV7 (KCNQ) are among those frequently associated with ASD. We hypothesized that these gating charge mutations would induce gating pore current (also termed ω-current) by causing an ionic leak through the mutant voltage sensor. Unexpectedly, we found that wild-type KV7 conducts outward gating pore current through its native voltage sensor at positive membrane potentials, owing to a glutamine in the third gating charge position. In bacterial and human KV7 channels, gating charge mutations at the R1 and R2 positions cause inward gating pore current through the resting voltage sensor at negative membrane potentials, whereas mutation at R4 causes outward gating pore current through the activated voltage sensor at positive potentials. Remarkably, expression of the KV7.3/R2C ASD-associated mutation in vivo in midbrain dopamine neurons of mice disrupts action potential generation and repetitive firing. Overall, our results reveal native and mutant gating pore current in KV7 channels and implicate altered control of action potential generation by gating pore current through mutant KV7 channels as a potential pathogenic mechanism in autism.

Interspecies transcriptomics identify genes that underlie disproportionate foot growth in jerboas

Current biology : CB

2021 Nov 12

Saxena, A;Sharma, V;Muthuirulan, P;Neufeld, SJ;Tran, MP;Gutierrez, HL;Chen, KD;Erberich, JM;Birmingham, A;Capellini, TD;Cobb, J;Hiller, M;Cooper, KL;
PMID: 34793695 | DOI: 10.1016/j.cub.2021.10.063

Despite the great diversity of vertebrate limb proportion and our deep understanding of the genetic mechanisms that drive skeletal elongation, little is known about how individual bones reach different lengths in any species. Here, we directly compare the transcriptomes of homologous growth cartilages of the mouse (Mus musculus) and bipedal jerboa (Jaculus jaculus), the latter of which has "mouse-like" arms but extremely long metatarsals of the feet. Intersecting gene-expression differences in metatarsals and forearms of the two species revealed that about 10% of orthologous genes are associated with the disproportionately rapid elongation of neonatal jerboa feet. These include genes and enriched pathways not previously associated with endochondral elongation as well as those that might diversify skeletal proportion in addition to their known requirements for bone growth throughout the skeleton. We also identified transcription regulators that might act as "nodes" for sweeping differences in genome expression between species. Among these, Shox2, which is necessary for proximal limb elongation, has gained expression in jerboa metatarsals where it has not been detected in other vertebrates. We show that Shox2 is sufficient to increase mouse distal limb length, and a nearby putative cis-regulatory region is preferentially accessible in jerboa metatarsals. In addition to mechanisms that might directly promote growth, we found evidence that jerboa foot elongation may occur in part by de-repressing latent growth potential. The genes and pathways that we identified here provide a framework to understand the modular genetic control of skeletal growth and the remarkable malleability of vertebrate limb proportion.

Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis

Cell death and differentiation

2021 Dec 02

Wang, T;Tomas, D;Perera, ND;Cuic, B;Luikinga, S;Viden, A;Barton, SK;McLean, CA;Samson, AL;Southon, A;Bush, AI;Murphy, JM;Turner, BJ;
PMID: 34857917 | DOI: 10.1038/s41418-021-00910-z

Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s) mediating motor neuron demise remain elusive. We recently established that necroptosis, an inflammatory form of regulated cell death, was dispensable for motor neuron death in a mouse model of ALS, implicating other forms of cell death. Here, we confirm these findings in ALS patients, showing a lack of expression of key necroptotic effector proteins in spinal cords. Rather, we uncover evidence for ferroptosis, a recently discovered iron-dependent form of regulated cell death, in ALS. Depletion of glutathione peroxidase 4 (GPX4), an anti-oxidant enzyme and central repressor of ferroptosis, occurred in post-mortem spinal cords of both sporadic and familial ALS patients. GPX4 depletion was also an early and universal feature of spinal cords and brains of transgenic mutant superoxide dismutase 1 (SOD1G93A), TDP-43 and C9orf72 mouse models of ALS. GPX4 depletion and ferroptosis were linked to impaired NRF2 signalling and dysregulation of glutathione synthesis and iron-binding proteins. Novel BAC transgenic mice overexpressing human GPX4 exhibited high GPX4 expression localised to spinal motor neurons. Human GPX4 overexpression in SOD1G93A mice significantly delayed disease onset, improved locomotor function and prolonged lifespan, which was attributed to attenuated lipid peroxidation and motor neuron preservation. Our study discovers a new role for ferroptosis in mediating motor neuron death in ALS, supporting the use of anti-ferroptotic therapeutic strategies, such as GPX4 pathway induction and upregulation, for ALS treatment.

TNF-α/ENO1 signaling facilitates testicular phagocytosis by directly activating Elmo1 gene expression in mouse Sertoli cells

The FEBS journal

2021 Dec 17

Xiong, H;Chen, Z;Zhao, J;Li, W;Zhang, S;
PMID: 34919331 | DOI: 10.1111/febs.16326

Phagocytic clearance of apoptotic germ cells (GCs), as well as residual bodies (RBs) released from developing spermatids, is critical for Sertoli cells (SCs) to maintain inner environment homeostasis within testis. However, the molecular mechanisms controlling the phagocytosis are ill defined. Here, we identify a new role for alpha-enolase (ENO1), a key enzyme during glycolysis, as a molecule that facilitates testicular phagocytosis via transactivation of the engulfment and cell motility 1 (Elmo1) gene. Using immunohistochesmitry and double-labeling immunofluorescence, ENO1 was observed to be expressed exclusively in the nuclei of SCs and its expression correlated with the completion of Sertoli cell differentiation. By incubating TM4 cells with different pharmacological inhibitors and establishing TM4Tnfr1-/- cells, we demonstrated that Sertoli cell-specific expression of ENO1 was under a delicate paracrine control from apoptotic GCs. In turn, persistent blockade of ENO1 expression by a validated siRNA protocol resulted in the disturbance of spermatogenesis and impairment of male fertility. Furthermore, using chromatin immunoprecipitation, electrophoretic mobility shift assay and luciferase reporter assay, we showed that in the presence of apoptotic GCs, ENO1 binds to the distal region of the Elmo1 promoter and facilitates transactivation of the Elmo1 gene. In agreement, overexpression of ELMO1 ameliorated ENO1 deficiency-induced impairment of phagocytosis in TM4 cells. These data reveal a novel role for Sertoli cell-specific expression of ENO1 in regulating phagocytosis in testis, identify TNF-α and ELMO1 as critical upstream and downstream factors in mediating ENO1 action, and have important implications for understanding paracrine control of Sertoli cell function by adjacent GCs.This article is protected by

Close Association Between Altered Urine-urothelium Barrier and Tertiary Lymphoid Structure Formation in the Renal Pelvis During Nephritis

Journal of the American Society of Nephrology : JASN

2021 Oct 22

Ichii, O;Hosotani, M;Masum, MA;Horino, T;Nakamura, T;Namba, T;Otani, Y;Elewa, Y;Kon, Y;
PMID: 34686544 | DOI: 10.1681/ASN.2021040575

Background: Kidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathological features of TLSs, including their formation and association with non-infectious nephritis, are unclear. Methods: RPs from humans and mice that were healthy or had non-infectious chronic nephritis, were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures. Results: Regardless of infection, TLSs in the RP, termed urinary tract-associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN-γ as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells via cytokine (IFN-γ, TNF-α) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction via the TNF-α/FOS/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development. Conclusion: TLS formation in the RP is possible and altered urine-urothelium barrier-basedUTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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