Analy­sis of the Chro­matin Acces­si­bil­i­ty Land­scape in Patients with Local­ized Prostate Cancer 

Ger­man Beat­riz, Ho Kun-Lin, Truong Tri, Gar­bari­no Jen­nifer, Ali Amina1, Azdze William, Elsamanou­di Sal­ly, Ng Col­in, Ches­nut Gre­go­ry, Ellis Leigh

Sig­nif­i­cant group-based vari­a­tion in prostate can­cer (PCa) out­comes remains a major glob­al health chal­lenge. African Amer­i­can (AA) men have the high­est inci­dence and approx­i­mate­ly dou­ble the mor­tal­i­ty of Cau­casian Amer­i­can (CA) men. Although dis­par­i­ties in health­care access con­tribute, worse out­comes per­sist even with com­pa­ra­ble care, sug­gest­ing bio­log­i­cal dif­fer­ences in tumor behav­ior. While emerg­ing stud­ies have begun to define epige­nom­ic alter­ations in PCa, the con­tri­bu­tion of large-scale chro­matin remod­el­ing to pop­u­la­tion-lev­el out­come dif­fer­ences remains unclear.

To address this, we pro­filed local­ized PCa from AA and CA men using sin­gle-cell spa­tial ATAC-seq and H3K27ac spa­tial CUT&Tag on prosta­te­c­to­my spec­i­mens from the Cen­ter for Prostate Dis­ease Research/​Walter Reed Nation­al Mil­i­tary Med­ical Cen­ter. Machine learn­ing – based anno­ta­tion (Cell­cano) enabled iden­ti­fi­ca­tion of lin­eage-spe­cif­ic chro­matin states. Fur­ther­more, AA demon­strat­ed sig­nif­i­cant low­er acces­si­ble chro­matin asso­ci­at­ed with CCCTCbind­ing fac­tor (CTCF) which is a crit­i­cal zinc fin­ger pro­tein cru­cial for reg­u­lat­ing gene expres­sion, epi­ge­net­ic marks, and main­tain­ing 3‑dimensional genome structure.

We have val­i­dat­ed this find­ing by CTCF immuno­his­to­chem­istry in an inde­pen­dent TMA that includes 99 patients with dis­tri­b­u­tion of CA and AA prosta­te­c­to­my sam­ples. More­over, inte­gra­tion of H3K27ac pro­fil­ing revealed sev­er­al dif­fer­en­tial­ly reg­u­lat­ed enhancer regions near spe­cif­ic genes across sam­ples. Col­lec­tive­ly, our cur­rent find­ings pro­vide crit­i­cal insights into the diver­gent chro­matin acces­si­bil­i­ty pro­files between AA and CA men with local­ized PCa, which like­ly under­lie dis­tinct tran­scrip­tion­al respons­es that can deter­mine ther­a­peu­tic resis­tance and tumor progression.

These data shed light on the com­plex epige­nom­ic mech­a­nisms dri­ving the group-based vari­a­tions in PCa out­comes and may inform the devel­op­ment bet­ter treat­ment strategies.

Ger­man Beat­riz, Ho Kun-Lin, Truong Tri, Gar­bari­no Jen­nifer, Ali Amina1, Azdze William, Elsamanou­di Sal­ly, Ng Col­in, Ches­nut Gre­go­ry, Ellis Leigh

Sig­nif­i­cant group-based vari­a­tion in prostate can­cer (PCa) out­comes remains a major glob­al health chal­lenge. African Amer­i­can (AA) men have the high­est inci­dence and approx­i­mate­ly dou­ble the mor­tal­i­ty of Cau­casian Amer­i­can (CA) men. Although dis­par­i­ties in health­care access con­tribute, worse out­comes per­sist even with com­pa­ra­ble care, sug­gest­ing bio­log­i­cal dif­fer­ences in tumor behav­ior. While emerg­ing stud­ies have begun to define epige­nom­ic alter­ations in PCa, the con­tri­bu­tion of large-scale chro­matin remod­el­ing to pop­u­la­tion-lev­el out­come dif­fer­ences remains unclear.

To address this, we pro­filed local­ized PCa from AA and CA men using sin­gle-cell spa­tial ATAC-seq and H3K27ac spa­tial CUT&Tag on prosta­te­c­to­my spec­i­mens from the Cen­ter for Prostate Dis­ease Research/​Walter Reed Nation­al Mil­i­tary Med­ical Cen­ter. Machine learn­ing – based anno­ta­tion (Cell­cano) enabled iden­ti­fi­ca­tion of lin­eage-spe­cif­ic chro­matin states. Fur­ther­more, AA demon­strat­ed sig­nif­i­cant low­er acces­si­ble chro­matin asso­ci­at­ed with CCCTCbind­ing fac­tor (CTCF) which is a crit­i­cal zinc fin­ger pro­tein cru­cial for reg­u­lat­ing gene expres­sion, epi­ge­net­ic marks, and main­tain­ing 3‑dimensional genome structure.

We have val­i­dat­ed this find­ing by CTCF immuno­his­to­chem­istry in an inde­pen­dent TMA that includes 99 patients with dis­tri­b­u­tion of CA and AA prosta­te­c­to­my sam­ples. More­over, inte­gra­tion of H3K27ac pro­fil­ing revealed sev­er­al dif­fer­en­tial­ly reg­u­lat­ed enhancer regions near spe­cif­ic genes across sam­ples. Col­lec­tive­ly, our cur­rent find­ings pro­vide crit­i­cal insights into the diver­gent chro­matin acces­si­bil­i­ty pro­files between AA and CA men with local­ized PCa, which like­ly under­lie dis­tinct tran­scrip­tion­al respons­es that can deter­mine ther­a­peu­tic resis­tance and tumor progression.

These data shed light on the com­plex epige­nom­ic mech­a­nisms dri­ving the group-based vari­a­tions in PCa out­comes and may inform the devel­op­ment bet­ter treat­ment strategies.

Analysis of the Chromatin Accessibility Landscape in Patients with Localized Prostate Cancer
Analysis of the Chromatin Accessibility Landscape in Patients with Localized Prostate Cancer
Analysis of the Chromatin Accessibility Landscape in Patients with Localized Prostate Cancer

Beat­riz German

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Beatriz German
Beat­riz Ger­man, IGBMC, France

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